All language subtitles for [English (auto-generated)] Mitochondrial Psychobiology [DownSub.com]

the chair of the the co-op uh in

neurology and um this is one of our

tenure talks um which is uh for uh

faculty members who are being considered

for tenure. Um it's part of the the

process of um of the doseier. It's um

and we're we're very excited to have

Martin here. Um our our esteemed

colleague Dr. Herano is going to

introduce him. But I uh um uh it's nice

to see everyone who's joining. Uh it's

nice to see some colleagues from

psychiatry where Dr. M Picard has a a

joint appointment and um we'll get the

ball rolling. Um Mitch, do you want to

say a few words of introduction for for

Martin?

You're muted if if uh

sorry about that. Okay. Yes. So thank

you Adam. So I'm very pleased to

introduce Dr. Martin Peicard for his

tenure talk today. Um and my

introduction is going to be a bit longer

than usual to highlight the uh

exceptional breadth and depth of Dr.

Peard's training and research. Um Dr.

Peard was born and raised in Montreal,

Canada. Uh he received his bachelor's

degree in physiology from McGill

University where he studied

neuroimunology under Dr. Julie

Desperatz. uh he then continued his

doctoral trainings on on or stud

doctoral studies on mitochondrial

biology of aging at Miguel under the

mentorship of Drs Tanya Tyasalo and

Russell he

uh Dr. Picard then did additional

fellowship training in systems biology

and oncology at Mc Miguel before

migrating to the United States to extend

his training in mitochondrial genetics

as a post-docctoral fellow in the

laboratory of Dr. Doug Wallace at the

University of Pennsylvania. In the in

the Wallace lab, Dr. Peard began his

investigation on the role of

mitochondria in response to uh

psychological stress using mouse models

of human mitochondrial diseases. This

seinal study published in PNAS has

served as a foundation for his ongoing

studies on the role of mitochondria and

psychological stress and his overarching

pioneering work in the new field of

mitochondrial psychobiology.

In 2015, Dr. Picard joined the

departments of psychiatry and neurology

as well as the HU merit center at

Colombia as an assistant professor. Here

at Colombia, Martin has uh bloomed

academically by applying his diverse

research toolbox to creatively and

broadly investigate the roles of

mitochondria in human mitochondrial

diseases, psychological stress, and

aging.

Uh in his first six years here at

Colombia, Dr. Bard has been remarkably

productive in mitochondrial

psychobiology. His multiple

accomplishments include development of a

mitochondrial health index to study the

mind mitochondria connection,

identification of self-free

mitochondrial DNA as a hormone that's

released in response to stress, uh

characterization of cellular lifespan

models, and demonstrating reversibility

of graying human hair in response to

life stress. And I think that's

pertinent to those of us who are turning

gray during this pandemic stress.

Uh Dr. Picard's current research on

mitochondrial psychobiology has five

bioenergetic themes. Mitochondrial

psychobiology to understand mind brain

interactions, aging, stress response,

self-free mitochondrial DNA as a hormone

and brain function and circuitry.

Uh on a personal note, I would like to

say that I've enjoyed working closely

with Dr. Picard both in the clinic where

he joins me weekly to see patients with

mitochondrial disease and in research

studies on human subjects with

mitochondrial diseases. Uh Dr. Picard

has published more than 90 papers at

many in high-profile journals such as

PNAS, EIE, Cell Reports and Major

Communications. His work has also been

featured in lay media including

Scientific American, the Wall Street

Journal, the Today Show and the New

Yorker. He's very well funded as a PI

and multiple PI of four NIH RO1s and R21

and a co-investigator in three three

collaborative RO1 and 1 grants. He's a

very popular speaker has given more than

40 international and national invited

lectures. He's received numerous awards

including a rising stars lecturesship

from the NIH director's office as well

as awards from uh the federation of

associations in behavior and brain

sciences and the academy of behavioral

sciences.

and throughout his work he's been an

open collaborator, generous mentor and

effective teacher. Uh just want to

mention also that Dr. Beicard's

excellent productivity led to his early

promotion to associate professor of

psychiatry and neurology in 2019. So I'm

now pleased to turn over the microphone

to Dr. Picard who will give his tenure

talk entitled mitochondrial

psychobiology.

Mio, thank you so much for uh a

wonderful introduction.

[clears throat]

Just going to share the screen.

So, it's really a pleasure to have the

chance to uh share my work today with

with everyone here from uh psychiatry,

from neurology, and others who've joined

the the call. Um I'm I'm uh very excited

uh not only to to share what we've done

but also to talk about uh the future

directions that that I I hope we take in

the future. But first um let's talk

about the the basis for what we do. And

really one major objective is to

understand determinance of health and

disease risk. And if we look at the pie

charts of what contributes to uh to

disease risk, a significant portion is

accepted to be coming from genetic

predisposition. But the major part of

this pie you will appreciate uh includes

behavioral factors, psychosocial

circumstances, environmental exposures

and access to healthcare. So the

majority of this pie includes modifiable

factors. And I think there's an a

tremendous untapped potential to prevent

and treat diseases and to promote health

before disease happens. And although

they are key to fulfilling I think the

promise of personalized medicine,

behavioral factors and psychosocial

factors have remained largely in the

periphery of biio medicine. And I think

in part, you know, progress in that area

has been hindered by the lack of

understanding of mechanistic

understanding of how psychosocial and

behavioral factors actually intersect

with human biology.

And some of the early uh scientific

influences that I was exposed to include

a series of papers including this one in

the New England Journal uh that was

showing how psychological stress

actually influences susceptibility to

the common cold. So if you inject a few

hundred people with attenuated uh flu

virus up the nose first not everyone

gets sick. So there there's a factor of

resilience there but those who get sick

are much more likely to experience and

to report higher level of psychological

stress and and in a related line of work

there was also a series of papers

showing that psychological stress can

slow down wound healing. Um and the the

link between psychological stress and

disease has been extensively studied and

was reviewed and this JAMA uh piece

which was excellent and uh Bruce Mcuan

has written also on how the brain uh

mediates this interplay between the

outside social world that influences our

biology and how the brain might play an

important role there. uh in in the last

uh decade or so a lot of progress has

been made in identifying neuroendocrine

psychonuroindocrinology

mechanism that connect the social

experience uh the human experience and

uh factors particularly related to the

immune system. So there are modifiable

factors that influence health resilience

and disease risk. But how does that

happen? How do those factors make their

way not only under the skin but all the

way inside the cell and inside the

nucleus where our genes are are kept? Um

so the dominant hypothesis I think in in

biio medicine has been that uh inherited

genetic variants contribute a large

fraction of disease risk and and

mortality. But we know now that there's

also a lot of other factors that

interact dynamically uh with our genome

including uh diet and and the food that

we consume, the behaviors that we engage

in, the environment that we uh live in,

the the social and psychosocial factors

including soioeconomic status and

adversity

uh and psychosocial factors are now well

documented to to influence these uh

various factors that ultimately drive uh

disease risk. And it's been argued in in

this beautiful paper that to put the

patient back together and really get a

full understanding of of disease risk,

we need to move beyond molecular

reductionism. All of our tools are great

to break things down. How do we put

those back to understand individuals as

people and then be most effective in

personalized medicine? And uh when we

think about how those pieces actually

fit together and what's the unifying

factor here uh it's striking to think

that our genes are brought to life by

energy. Right? The the major

differentiating factor between a

thinking uh feeling conscious person and

a dead body a cadaabver is really the

flow of energy through the organism. And

energy flow is actually what connects

parts into holes. What allows

communication between different parts of

of the whole organism. uh and in

breathing creatures like humans, energy

comes from mitochondria. Uh so

mitochondria and their ability to

transform energy and and to communicate

uh potentially is the glue that binds

all of these aspects of of human health.

So what I'm going to share with you

today is our progress that we've made to

test some hypothesis related to

mitochondria and mitochondrial

psychobiology. and I'll present five

main themes like Mitchio nicely

introduced. Uh but before I get there, I

want to say a few words about the

background that led us to uh to this

research project. So as Micho said, I

was fortunate to have a fairly diverse

uh training uh at Miguel University

initially in her immunology and in

mitochondrial biology of aging. And I I

was trained by Tanya who was an expert

in mitochondrial disease and exercise.

Ross Heel who uh was a mitochondrial

biology aging expert. Yan Murel who had

been trained as a classical

mitochondrial physiologist and

transferred his his love of

mitochondria. Uh Orientai who's an

expert of mitochondrial dynamics and has

been a wonderful mentor. I also received

training in health psychology and

integrative medicine from Katherine

Sabistston and Judian McNamera. Uh and

Doug Turnbull in Newcastle University uh

welcomed me midway through my PhD uh in

in his lab in England um where I could

learn about mitochondrial genetics. And

one late evening after the the lab was

closed and the microscope was free, I

took this video. Uh what you're seeing

here is a living cell uh with all of the

little squiggly spaghettes. Here are the

mitochondria, right? moving, dynamic,

full of life. Uh, and this century here,

it it struck me at the moment, this is

where the genome lies, right? This is

where the the pairs of chromosomes are.

And this is where the environment is,

right? Outside the cell. Mitochondria,

this dynamic network of mitochondria

lies in between the inside of the cell

and the outside world. Uh so the the

question that that came was well could

mitochondria be the X factor in the gene

environment uh diad that actually

contributes to health and this became

the motivation to uh for a lot of the

work that I did in my PhD trying to

understand mitochondrial uh form or

structure and the function of of the

mitochondria. And perhaps the most

important experiment I did was where I

perturbed the morphology of the

mitochondria and imaged here what we're

seeing isolated mitochondria. So in

three dimension I was able to document

the changes in the morphology and then

along with this document the changes in

the function. So this showed that uh

changing the shape of the mitochondria

actually changes their function. And uh

and also the key lesson for me was that

methods and that we use influence the

mitochondrial outcomes which has become

useful as uh we continue developing new

methods. Another important formative

experience was working on what's called

ventilator induced diaphragmatic

dysfunction which is an important

clinical problem especially in this day

and age. If you mechanically ventilate

someone put someone on a ventilator can

save the person's life but the diaphragm

suffers consequences from this. And what

I found was that this was associated

with a proliferation of bad

mitochondria, mitochondria with

mutations in the mitochondrial DNA,

which is what we see here as this blue

segment. The blue mitochondria are sick,

the brown one were normal. And I found

that the blue mitochondria could

actually proliferate quite quickly. And

the lesson here was that mitochondrial

defects are clinically meaningful and

potentially a broad spectrum of

disorders and not just in a rare group

of mitochondrial disorders. uh through

my training I became a little obsessed

with imaging mitochondria and trying to

understand what they look like and how

they might uh function and I had the

opportunity to do uh microscopy at using

a number of different methods and I came

across this observation that

mitochondria could actually synapse with

one another almost like with as gap

junctions uh and these are called inter

mitochondrial junctions and that was

actually the rediscovery of something

that had been discovered in Russia back

in the 70s u and I developed a new

method uh building on this to

quantitatively define mitochondrial

morphometry um which then

uh made me interested to uh expand

beyond the mitochondria and go for

post-docctoral training with Doug

Wallace and Doug had discovered that we

just we get our mitochondria from our

mom so we all have her mother's

mitochondrial DNA and had used that

information to map the migration of

humans out of Africa uh and then later

had showed that mitochondrial DNA

mutations were the cause of human

disease. So when I went to Doug's lab, I

wanted to do three things. One, continue

working on mitochondrial communication,

learn about mitochondrial genetics, and

then learn methods and epigenetics.

So the first question I asked as a

postto was how do mitochondria talk to

each other and to the epiggenome inside

the cell nucleus? And what we're looking

at here is an electron tomogram. So it's

three-dimensional electron microscopy.

And in the middle there's a

mitochondrian. And I hope you can see

that the christe here that this the guts

of the mitochondria are curving and

bending to align with the the christe of

the surrounding mitochondria. So this

was the first physical evidence that

mitochondria exchange information with

each other. And at the same time I was

doing imaging of mitochondria and other

tissues and uh observed the striking

fact that mitochondria very often

connected by those mitochondrial

synapses lie right there at the

interface of the nucleus and uh the

outside world of the cytoplasm and very

often being only few hundred nanometers

away from the chromatin the the

epiggenome. And I did a cellular study

using cytoplasmic hybrid cells then

where I was able to manipulate the level

of mitochondrial dysfunction or mutation

load and showed that if you increase

mutation load a little bit, it

completely shifts the cellular

transcript gene expression in one

direction and then if you continue to

shift mitochondrial uh mutation load

that eventually sh cells shift towards a

completely different behavior. Uh so

this showed strikingly that by uh

tweaking the mitochondria we were

tweaking over twothirds of the human

genome the expression of twothirds of

the of of the human genes and uh this I

think helped to us to understand

mitochondria are not passive powerhouses

but they're actually dynamic

communicative organels that shape

cellular gene expression and behavior.

And that those findings came around the

same time that it was becoming clear

that mitochondria actually speak the

language of the epigenome for

evolutionary reasons. All of the

modifications that happen on the

chromatin uh come from molecules that

are metabolized or produced by

mitochondria. And I started to draw

inspiration from the field of

neuroscience and uh thought about uh the

brain as and the way that neural

networks actually receive information

from the outside world. sensory inputs,

environmental signals, process and and

compute information from those and then

produce intelligent outputs,

neuroendocrine outputs that coordinate

the organisms function. So I started to

think what if mitochondrial networks

could do something similar. They would

receive metabolic endocrine inputs from

the the outside world as well as energy

levels and then through their

interaction, their physical interaction

with each other, integrate, process

information, maybe uh do some kind of

memory formation and then produce

intelligent outputs that would uh guide

cellular behavioral behavior through

changing gene expression. And then in

the context of wanting to understand the

transduction of psychological stress

inside the cell, this motivated a

project looking at stress responses in

animals. So here I used mouse genetics

to ask whether mitochondrial defects

could change how organisms how animals

respond uh to to stress. So with uh my

fellow colleague postoc Megan Mcmanisen

uh I used five different strains of mice

with different mitochondria and then

exposed them to a brief stressor. So you

see here for 30 minutes there's a stress

that's applied in black or the mice with

the normal mitochondria blue and red or

mice with different types of

mitochondrial defects. And what this

experiment showed is that by tweaking

the mitochondria, we're actively

tweaking multi-system, multi-organ

responses that involve the brain and

other peripheral glands. And collecting

data on a couple a few more dozen stress

reactivity uh measures, we were able to

show that uh tweaking the mitochondria

not only exaggerate or doesn't just

exaggerate the stress response, it

actually qualitatively tunes uh how the

organism perceives responds and enacts

uh the stress responses. So this was

starting then to make possible the fact

that mitochondria could contribute by

their ability to sense information, to

process information, to produce signals

to the biological embedding of life

exposures. And this is an important

question that u a lot of people are

working on in in other fields. How does

the environment get under the skin? And

fundamentally an interdisciplinary

question as well. uh like Mo mentioned,

I had the chance to train in

psychosocial sciences and in systems

biology and had the chance to learn to

think across disciplines uh about

transdisciplinarity.

And one particular uh piece that I want

to highlight is is this one with Robert

Paul Jester and Bruce Mchuan uh where I

uh asked whether the mitochondrial

allostatic load. So the the accumulation

of of recalibration structural

functional changes in mitochondria could

actually explain why psychosocial stress

leads to stress pathophysiology and is

bad for health. So this led to this

access of stress mitochondria disease uh

and really became the foundation for

starting my lab at Colombia in 2015. So

when I came to Colombia I was really

excited uh for many reasons but one of

those reasons was because of the long

history uh and neurology of research in

mitochondrial disease and mitochondrial

biology uh including people like Daryl

Devivo, Billy Demorro and Eric Shon all

of whom have been incredibly supportive

uh since I started. And what made this

possible was Richard Sloan who trusted

me to join his division of behavioral

medicine and psychiatry. Mito Herano who

trusted me to join his division of

neuromuscular disorders and neurology.

Uh and I was also lucky to have

continued mentorship from Alyssa Epel uh

who is an expert of stress and aging,

Bruce Mcuan who's many people consider

the father of stress neuroendocrinology

as well as Orian and Doug. Um, and

Orian's input became particularly

valuable when I submitted my first NIH

grant uh in 2014 and uh I sent my grant

to Orian and then he said this is very

nice uh but this is not a grant. Uh so I

was a bit deflated uh revised

extensively sent it back to him and he

said this is a little better. Um so in

the end the grant uh was funded and this

uh you know set up um uh helped to set

up the lab to uh to start uh working on

on important things. And so the master

plan then became the following. First we

would develop tools and approaches to

quantify mitochondrial health and

signaling in humans. Then we would use

these tools and approaches to map

mitochondrial psychobiology mechanisms

the mind mitochondria connection and

their relevance to human aging. Then we

would apply those mitochondrial

psychobiology principles to gain

clinically meaningful insights into an

area of medicine that uh is remains uh

for which there's no cure at the moment

which is mitochondrial diseases and then

we would leverage these insights from

mitochondrial disease to understand the

basis of health not the absence of

disease but human health and then

accelerate the transition towards

sustainable health care.

So this is how I've organized my

thinking around uh this fairly broad

question from organal to organism. uh

recognizing that mitochondria talk to

each other and with the cell nucleus and

which is what I showed driven by my

postoc and then this influences in turn

how cells behave and the ability of

cells to talk to each other and then the

the ability of cells to work together

influences organ level function

including stress responses in in animals

and brain function and this is

paramount to how individuals um

function and behave and interact with

each other and then which is in turn uh

fundamental to being able to create

healthy societies and and communities uh

that maximize human potential and

development. So the first thing I wanted

to do in my lab was to expand uh my

earlier work to clinically relevant

questions and there's a series of papers

that we produced in in the first uh four

years first where we described

mitochondrial nanot tunnels which are

these thin tubular structures that

connect mitochondria to each other which

hadn't been described in humans and we

mapped the life cycle of mitochondria

that contributed to shift or view again

of mitochondria as communicative

organels. We also described the spectrum

the the the amazing beauty of

mitochondria and mitochondrial disease.

Uh we mapped the three-dimension

mitochondrial network. For the first

time we were able to see and to quantify

what mitochondria look like in human

tissues and in mitochondrial disease. uh

and we partnered with Eric Handell and

um we're able to also map uh

mitochondrial morphology in three

dimension inside uh neurons and u and

finally uh we were able to use that

knowledge and and uh and that

observation I had made in the diaphragm

in the human diaphragm several years ago

uh to identify mechanisms of

proliferation and propagation of

mitochondrial defects. So and we found

that mutant mitochondria exhibit

cancer-like behavior and that they they

proliferate um by signaling to the

nucleus driving their own proliferation

and then spreading through the

mitochondrial network that that we had

mapped. So this established the

relevance of mitochondrial signaling in

mitochondrial diseases and also in in

human aging. So having established this

then the next challenge was to bring

this closer to the human experience and

to other areas. So the the first uh

question that I wanted to start asking

was well how do we develop

inter-individual how do we map develop

methods to map inter individual

differences in mitochondrial health and

this is initially was supported by an

Irving scholars uh program award and

what I did there was to use

wellestablished methods to measure the

enzyme activity in the mitochondria

increase their their throughput and then

use fairly simple computational methods

to integrate energy production capacity,

mitochondrial content into this

mitochondrial health index, this MHI.

Um, and once we had a way to quantify

mitochondrial health, then we can put

this in relation to psychosocial

measures and ask whether there's a

connection between how people feel and

and their mitochondria and the white

blood cells. And this led to an

important paper from my lab which showed

that this mitochondrial health index is

indeed sensitive to mood and to chronic

stress. And what this showed by

measuring how people feel every day for

a whole week and measuring mitochondrial

function on day four, we found that uh

how people reported feeling more

positive uh the days before mitochondria

predicted mitochondrial health. Uh but

mitochondrial health did not predict how

people felt the days after. So this

showed that up to 12 to 15% of the

variance right of differences between

people uh in mitochondrial uh energy

production capacity could be driven by

how people feel. So this was the first

directional evidence of a mind

mitochondria connection. And around that

time I was working on a review to uh

systematically uh review the the

literature on different parts of this

model uh from stress to mitochondria to

to disease. And I was asked to extend

this to a two-piece series uh and then

link this also to established uh

concepts in in psychonur endocrinology.

And this is when the the the third

mitochondrial psychobiology came to be.

So up until then my lab had been the

mitochondrial signaling lab and then the

lab became the mitochondrial

psychobiology lab. And with this

rebaptized lab, we revised our mission

statement and our goal became to

identify novel principles that connect

molecular processes within mitochondria

with the human experience, thereby

enhancing our understanding of brain

body interactions to promote health

across the lifespan. And it became clear

that to achieve this goal uh we would

need to rely on collaborations because

we don't know everything about

everything. uh we would need to focus on

innovating both on methods front and on

the conceptual front integrating uh

information across disciplines and also

conductor work with the highest standard

of excellence and uh academic integrity

and this was facilitated uh by having

labs in two different areas one in cold

four on the cold research annic this red

brick building by the neurological

institute where we share the floor with

Dave Salser's lab and uh where we can

profile the mitochondria deploy deploy

our mitochondrial phenotype phenotyping

platform and another lab space in

Richard Swan's division on PH15 and 16

where we can bring participants and

actually get information about people's

um subjective experience and then we can

collect precious samples blood saliva

other bofluids bring those over to cold

profile the mitochondria bring that data

back over to to PH and in a way complete

have this flywheel that allow us to to

ask uh good questions about

mitochondrial cycle biology. So now I'll

tell you about uh progress that we've

made in five main areas. The first area

is mitochondrial disease and our work in

mitochondrial disease area has has been

supported initially by a collaborative

and multi-disiplinary uh pilot grant

from the Irving Institute which led to

an R21 which led to an RO1 for the MSBY

study uh and uh more recently by a pilot

award from the New York Nutrition

Obesity Research Center and this

supported the Misb study at the

mitochondrial stress brain imaging and

epigenetic study which has been ongoing

for four or five years and it's the most

ambitious project of of my lab and

involves pretty much everyone in in the

group. And what we're doing here is

basically the human translation of the

mouse study that I mentioned earlier

with the highest degree of genetic

specificity we can achieve in in humans

uh using individuals who have uh

specific known defects genetic defects

in their mitochondria. So we can ask if

the mitochondria are perturbed do we

change how how people uh respond to

stress and and um and respond as as as a

whole person. So we profile

mitochondrial health extensively and

then we measure stress reactivity,

multi- system responses and profile the

number of disease biomarkers and at the

same time we profile brain structure and

function, mental health and their

psychological function and this project

was uh made possible with the

collaboration with Misho that he

mentioned and the infrastructure that

Richard had in place in the division.

This is in a nutshell the Bisby protocol

which I'm not going to go through but

it's two very intense days and we tell

our participants we want to understand

you as a person. Uh and a lot of things

happen for the participant it's

full-time 9 to5 uh they stay at a hotel

nearby and at the same time in the lab

all of the samples are being processed

for each participant that comes in we

store 162 samples in the bio bank. we

have this beautiful uh multiorgan stress

reactivity profiling and then patients

go home and then at home they collect

more data to send later and our

objective here as I said is to

understand each participant as a whole

and to capture their their experience

and how it relates to what happening in

in their mitochondria this is the team

the it's a whole choreography and it

involves people from my lab peoples from

uh Mitcho's lab and people uh from

Richard's lab this is the team of

investigators that I've assembled to

bring expertise and epigenetics,

neurosychology, clinical psychology, uh

stress psychophysiology, neuroiming,

mitochondrial disease and mitochondrial

signaling. And what's really exciting

about MSBY is that it's the first human

study to link mitochondrial bionetics

with psychobiology. And it has, I think,

real potential to yield new insights

into mitochondrial disease biology. uh

and recently we've started the

mitochondrial daily energy expenditure

study the MDE study uh which is adding a

layer of of analysis to to misbe where

we un uh we measure energy expenditure

and how much how much energy it costs to

stay alive for for our participants and

the MDE team also is a wonderful

collaboration uh where I've engaged

people from the department of medicine

uh who have expertise in energy uh uh

expenditure measurements and body

composition.

The second theme I'll discuss is aging.

And our work on aging has been supported

initially by a fellowship from the

Colombia Aging Center and then more

recently by an RO1 uh from NIA. And uh

I'll talk about two main themes. The

hair mentioned uh the hair is beautiful.

It it's part of the organism. The hair

follicle is inside the skin. So it can

absorb information as it grows out. Then

it crystallizes our biological history

into this hard shaft that sticks around

as long as we as we don't cut it. And

there's also these, you know, anecdotal

reports and some people can relate to

this um where stress can maybe

accelerate or trigger the graying of of

hair. Uh is there something to this?

There up until recently had not been

good quantitative assessments of this.

So we developed an approach to to

measure this. Uh and what we're going to

see here is uh a video of moving along a

single hair. This is a hair from a

participant uh a 35year-old female. Uh

you see the hair was dark initially then

it turned gray. So we can position along

the hair you know when exactly the

graying happened and then you can see

the hair is gray and then at some point

you start to see some pigmentation

coming back

and then the hair under goes full

reversal. to its original uh color. So,

we've quantified this. We developed an

approach to to digitize the hair

pigmentation pattern. You can see here

the hair was dark, that it's white, and

then it's dark again. And we coupled to

this an assessment, a retrospective uh

kind of time anchored assessment of

stressful life events. And this

participant said, well, you know, I

finished my thesis, was not too

stressed, and then the most stressful

two months of my life happened. Right?

She had a personal breakup, some uh

personal hardship, had to cross, you

know, travel across the country and and

so on. Um and then the stress went away.

She moved to New York City and um and

all good and the hair turned back to

dark. Uh and we saw we have a few

examples like this. And what this uh

study did was to show that the hair gray

at least temporarily is reversible and

provided the first quantity of evidence

that um that gray can be reversed in

humans. Uh like Mitchell mentioned, this

was covered uh both in um in in

Scientific American and uh on on the TV.

And I I'll let you hear what the the

anchors have to say about this.

>> Some new scientific research that there

might actually be a way that reverses

the gray of the hair. You know, when you

get pull it out

on

original pigmented.

>> So what happened there is something that

seems to happen in quite a few people

since this aired and and since the paper

was published I received a number of

emails of people who said thank you for

validating my experience. people were

telling me I was crazy but this actually

happens. Uh so the paper made three I

think important contributions. One it

showed the hair grain and maybe other

aspects of human aging are malleable and

temporarily reversible. Uh that hair

grain is linked to mitochondrial

recalibrations. We did proteomics in

single hairs to to show that there are

changes in mitochondrial proteins uh and

linked to psychological stress. Then I

wanted to start investigating this a bit

more mechanistically uh in in vitro uh

asking whether we can follow

trajectories of aging over time. And for

this we developed a cellular lifespan

system where we can take skin

fibroblasts from from donors put them in

a dish and then every so often collect

cells and basically uh recapitulate the

launch longitudinal trajectory. And this

was leveraging my original observations

that the mitochondria were very close to

the nucleus could change gene

expression. And I combined a team uh

including the inventor of the epigenetic

clock Steve Forvat and other uh

statistician and people from mathematics

to to generate mathematical models of

trajectory over time. Uh time course

data can be challenging. uh and then

Gabriel in the lab did this amazing uh

feat where he treated cells with a v

variety of treatments that either

targeted mitochondria or other pathways

to ask how does this change aging. So

the study design is is as follows. uh

you can sequentially passage cells and

also collect data on multiple different

accounts including cell behavior,

energetics, DNA measures of aging and

and epigenetics and mitochondrial

damage, gene expression with RNA

sequencing. Then you can sample the

media the same way you would take blood

draws in in humans. You can sample the

media to ask what the cells are are

secretreting and producing. And what

Gabriel did was to do this in healthy

controls, fibroblast from healthy

donors. do this in cells that came from

Mitio's lab of patients that had

mitochondrial defects and then use an

alternative orthogonal approach using

pharmarmacology to perture the

mitochondria and ask how does it change

the aging trajectory and this led to an

amazing uh finding that when the

mitochondria are dysfunctional cells go

uh into this hyper secretary state where

they start to secrete a number of

proteins including mitochondrial DNA so

the mitochondrial DNA that's normally

inside the mitochondria becomes spat out

and outside the cell. This is associated

not with a slowing down of gene

expression but an acceleration of stress

response pathways and this costs energy.

Maybe unsurprisingly, but this is a new

concept in in the area of of

mitochondrial dysfunction that the the

defect in the mitochondria actually

increases the total amount of energy

necessary to to sustain life. And what

we were able to to show with this

longitudinal model was that the rate of

cellular aging based on the hay flick

limit, based on the telomeir shortening,

based on the epigenetic clocks is

accelerated. If you perturb the

mitochondria, it costs more to live and

it also accelerates the rate of aging.

We've since then uh collected and and

metaanalyzed data from over 15 studies

from collaborators from all over the

world to find that this is also very

likely to be conserved in in patients in

humans with mitochondrial disease and

that uh is called hyper metabolism.

Right? So there's an acceleration of the

rate at which information which energy

is being consumed in the organism and

which could explain some of the symptoms

in patients who mitochondrial disease uh

who are very rarely obese tend to have

short stature be tired all the time and

so on. So this is now leading to an

interesting hypothesis that hyper

metabolism could contribute to symptoms

and to perhaps early mortality in

mitochondrial disease and we have two

ongoing studies that are testing this

idea.

The third team I'll mention is self-free

mitochondrial DNA or CF mitochondrial

DNA. Uh and this has been supported by

uh an R1 from NIMH uh and more recently

an R21 to expand on this. And this line

of work really started with this paper

that was led by Kevin Trump who was then

a postoc in my lab uh in collaboration

with Anna Marsland who is a

psychonurinologist and had studied how

psychological stress triggers

inflammation for about 20 years and uh

Anna had samples in her freezer that we

thought let's assay them for cell free

mitochondrial DNA and perhaps

psychological stress five minutes of it

would be sufficient to trigger the

release of self-free mitochondrial DNA

into the blood. uh the acute

psychological stress successfully

increase anger increased anxiety. So

manipulating the psychological state was

successful self-free mitochondrial DNA

also increased 30 minutes after the

challenge. Do this again one month later

in the same individuals uh and uh that

validated the the original finding. So

this led to the idea uh that self-free

mitochondrial DNA could be a stress

hormone something that mitochondria

release in respond to to psychological

stress that then go out and goes out

into the organism to uh to affect

physiology and pathophysiology. Uh this

was covered in scientific American uh

along with some other things uh to

suggest that

release mitochondrial DNA could be

functionally relevant. And this

attracted attention maybe not just more

you know in the public media but uh also

in the scientific community there's

growing interest for cell free

mitochondrial DNA and we've done a

particularly careful job at

operationalizing every step uh that

needs to happen from blood draw to

measuring the mitochondrial DNA um at

the end of of the pipeline and uh

examining the influence of different

steps on the the final readout. And

we've used my lab's expertise in imaging

to understand where the mitochondrial

DNA is coming from. Uh and also

systematically analyzed a potential

source of technical biases that that

exist in the existing literature uh and

provided minimum reporting guidelines

and recommended procedures to help

harmonize the field of cell

mitochondrial DNA research in humans.

And this we're applying already into a

new study called the mitochondria and

psychological stress study in

collaboration with my colleagues Brett

Kaufman and Adam Marceland who are FPIs

on this project. Uh which is a

controlled crossover design experimental

trial on the effect of acute uh

psychological stress on cell free

mitochondrial DNA in healthy women and

men. and in interacting with uh people

in the psychonurology field I became

well aware that stress hormones and

metabolites are often measured in

saliva. Uh so we started to think what

if cell free mitochondrial DNA which is

probably u you know important for

several uh disorders could be measured

in saliva right if this was the case

this would make possible epidemiological

studies uh where you need to use

non-invasive methods and high temporal

resolution time course studies of cell

free mitochondrial DNA to to quantify

the dynamics uh of this signal and uh

and so we have a new grant to to start

this and the answer is yes cell free

mitochondrial DNA is measurable in

saliva and there's tremendous amount of

dynamics there that we're just starting

to map.

The next theme I'll talk about is the

brain. U and I don't know much about the

brain but luckily others do and I've

been able to to partner with them. And

originally Phil when he moved to

Colombia asked me to be to contribute

some mitochondrial expertise to his

fantastic U1 team and then I received a

pilot award um along with colleagues in

psychiatry to develop a new project and

we have a pending RO1 uh for this. So

I'll just uh mention three uh projects

briefly that relate to this. The first

one uh is basically the translation of

the mood to mitochondria finding that I

I talked about earlier with MHI and

blood cells. Now Cavalin has started to

ask whether this is also true in brain

mitochondria. So the psychosocial

exposures uh influence brain

mitochondria using proteomics and 400

human brains. that's done in close

collaboration with Hans Klein and Phil

the Jagger. Um we Kalpita also started

to ask whether mitochondria could signal

not just through labile signals but by

shipping pieces of DNA that get

incorporated uh like retrotransposons

into the the nuclear genome and that

seems to happen and to have relevance

for uh for disease outcomes. Uh and then

finally uh I let brought our

mitochondrial phenotyping platform to

the next level uh in a record number of

samples over 500 to map brainwide the

properties of mitochondria across the

mouse brain. And what this showed is

that mitochondria again are not all

created equal and there are different

kinds of mitochondria that respond to

stress in different ways uh that are

distributed in different parts of of the

brain. Uh so this motivated us to bring

this work into the human brain and to

launch this project called the my

mitorain map v 1.0 which is a

multifunctional mitochondrial atlas of a

single human coronal brain section at

fMRI resolution. So many of you have

probably seen this the I think this is

really when for me the human brain the

beauty of the human brain really set in

this is absolutely gorgeous. Then how do

we profile mitochondria in the human

brain like this which is frozen? This is

a piece that's at minus 20 degrees CC.

Well, uh the solution, one solution is

to voxalize the brain into small cubes

the same way that fMRI does digitally

and then if we have little cubes over

700 of them for a single section, then

we can deploy your mitochondrial

phenotyping platform, deploy cellular

profiling methods uh and then apply um

methods to bring data uh in those cubes

into standard stereotactic space uh

that's used in uh functional neuro

imaging. And this work has been a

fantastic collaboration that's made

possible in large part by Eugene

Masherov in psychiatry in Dave's lab um

who developed a software hardware

platform to turn a frozen piece of brain

into little cubes that our team in

collaboration with Phil's uh in

collaboration with our colleagues at

psychiatry who are doing hisystology in

those brains uh and Michelle Cibo who's

u doing the um transfer of those data

into M&I space and so what this project

is doing that I'm really excited about

is that it's closing the gap between

organel or bioeneroggetic profiling that

my lab has become good at and whole

brain neuroiming modalities that a lot

of people use to understand uh the link

between brain and behavior in humans and

we're also addressing uh this brain

related questions in NISBY uh where we

collect brain structure and and function

data where we can ask how do

mitochondrial DNA defects and mutations

affect the human brain circuitry and uh

where our goal is to develop a

neurologic signature of mitochondrial

disease. And in fact, we have

preliminary evidence that we might be

able to tell who has mitochondrial

disease and who doesn't just based on

functional activity patterns in the

human brain uh during resting state. And

we have a grant pending to extend those

studies into the the Ross Mapap cohort

uh in relation to Alzheimer's disease.

So the last theme that I'll uh touch on

is technological innovation that makes

possible some of the other things that I

just mentioned. And the most significant

contribution we've made here is this

recent paper where we phenotyped

mitochondria in different types of white

blood cells in the human circulation. uh

so we've developed an approach to to

quantify the mitochondrial phenotypes or

what we call mitoypes in different types

of lymphocytes activated naive B versus

T cells u and other types of of uh

adaptive innate immune cells and we've

also started to apply those approaches

longitudinally so if you if you have a

highly compliant participant who gives

blood every week you know what are the

week-toeek changes in those parameters

in a cell type specific manner in a

mitochondrial

outcome specific matter. So this study

has provided cell type specific uh

measures of effect sizes, temporal

dynamics and relation associations with

sex and age and standard classic

biomarkers. And what this is doing is I

think providing foundational data to

design highquality human mitochondrial

studies not just for mitochondrial

psychobiology but uh for biio medicine

more broadly. We have also not known as

as a field whether women and men have

different mitochondria, which is crazy

given that there's been decades of of of

research in in mitochondrial biology.

and Alex in our lab uh completed a study

recently where we pulled data from

generous collaborators who agreed to go

back to their old data set, sent us data

from over 50 papers and labs uh over

2,000 people and then asked

systematically are there differences

between women and men mitochondria

across a number of domains of

mitochondrial biology the same way we

would break down domains of of human

health. And the the answer is yes. There

are systematic differences but mostly we

the field hasn't captured and hasn't

looked at uh sex as a continuous

variable and hasn't started to look at

gender um which is a big gap in

knowledge. And finally the the last

piece that I think we need to crack is

understanding how things change over

time. There's so much to learn from time

series and in the MDE study uh we're

performing multifphysiological

measurements and among other things we

collect saliva and blood. So that allows

us then to look at whether those are

correlated over time. So we can validate

biomarkers in saliva whether they

reflect the blood or whether they

reflect something else. And here we're

seeing a fairly good correlation. This

is cortisol and this is cell free

mitochondrial DNA. And here the the

resolution is every five minutes. So you

can appreciate that the level of

cell-free mitochondrial DNA can can vary

up to an order of magnitude within

minutes. uh which is bringing a

completely new understanding of uh the

dynamic nature of mitochondrial

signaling in humans.

So our our work in in mitochondrial

psychobiology recently was covered in in

the New Yorker um and with a particular

emphasis uh about the gap of of

understanding between what happens at

the level of mitochondria energy and

what happens when people say I have a

lot of energy or I feel I have zero

energy. Um and um this

yeah the writer did a great job on this

piece. Uh finally I wanted to uh share

this video that was made by a former

postoc in in my lab uh that introduces

some of the the team members.

[snorts]

>> I didn't have a very good understanding

of mitochondria. I just knew the

powerhouse of the cell thing that you

learn in bio. Mitoonia are involved in

many many functions very important to

cell survival and epigenetics.

>> It's like a whole community talking to

each other and moving around and it's a

whole world within a world.

>> Cell types have their mitochondria

function differently depending on where

the cell is. So heart cells their

mitochondria functions completely

different than mitochondria in the brain

and skeletal mitochondria. In the lab,

[music] we have projects that span

everything from molecular and cellular

processes all the way up to thinking,

feeling organisms. I studied the

association between psychological stress

and mitochondria. So, we discovered that

mitochondria in response to acute

psychological stress can release their

own DNA into circulation.

>> I'm working on two projects in lab. One

is studying hair pigmentation patterns

and how that might correlate to stress

and maybe mitochondria. one in studying

[music] the effects of stress on

mitochondrial health in mice. In the

lab, they're looking more at how

approximations of stress can affect the

cells, but then the part of the study

that I'm working on is looking at how

psychological stress affects

mitochondria. We're working with a nurse

collecting blood. And so, we get to look

at even smaller physiological markers of

stress.

>> It's going to look at the different

white blood cells, whether they

activated or nonactivated. And then

we're going to use this mitochondrial

health index to try to see how these

particular lucasytes use their enzyatic

activities.

>> We think that cells perceive time using

their mitochondria. So what we try to do

is play with the mitochondria and see if

it makes them lose track of time or

speed up time or slow down time.

>> You really see how much an

interdisiplinary

approach you can take to studying

mitochondria because it's so involved in

everything. It makes sense for this to

be a focus probably for any study that's

looking at biological samples. There

really is so much more to mitochondria

within the body.

>> So you you heard the plurality of voices

in the lab uh people at different stages

of training. This is our wonderful team

that I just want to briefly introduce.

Uh we have a couple grad students

Natalia and Jeremy who were working on

stress uh and aging cellular projects

and a self free mitochondrial DNA.

Gabrielle who uh was a wonderful

undergrad uh student in the lab who's

now at Berkeley but has a a couple

papers still in the works. Uh Snehal and

Ilet who also are now medical students

and graduate students uh who also have a

paper still in the works. We have a

great team of research assistants and

research nurse, Marissa and Katherine

who are the Misb study coordinators.

Leah who is our research nurse who draws

the precious blood samples that we use

at MSBY. Um

Marlin who is our lab manager and

process samples uh with Anelie who's

also leading our new saliva study, Alex

who's done the work on the sex

differences and mitochondria and is

applying the mitochondrial phenotyping

platform to brain samples. Shannon who's

leading the MDE study and was

instrumental in the hair project. Uh

Grace who's data manager for our

division. We have a couple undergrads

Sophie and Rohan who work with Carolyn

and Anna posttos Kalpita just recently

moved to Cornell after finishing her her

postoc and she still has a couple papers

in the works. Anna who came with stem

cell biology background who's working

closely with Phil's lab to bring our lab

into the single cell biology world and

Alex who's uh working at understanding

hyper metabolism and energy expenditure

in cells and in people. uh we have an

assistant professor Kavalin uh who I'm

delighted after four years of training

as a mitochondrial psychobiologist

decided to stay with the lab uh and to

bring uh mitochondrial psychobiology

into the world of epidemiology and she's

doing a fantastic job at that and we

have two important consultants uh Noah

who has over two years of experience now

uh and uh my lovely Mary who is a

neuroscientist by training and and

social scientist who who helped take

care of this wonderful family.

So this is the overview of our progress

uh over the last six years since uh I

joined Colombia. So at the moment I'm

leading a number of of large projects

that uh I'm confident are going to bring

you knowledge about the role of

mitochondrial biology uh in psychiatry

in relation to mental health and

relation to uh questions regarded the

brain and mitochondrial disease. Um and

uh since uh since I made the

observations that mitochondria have

dedicated structure to share

information, we've then expanded that uh

into studies to understand the relevance

to cellular aging to psychobiology and

and stress responses and v variation

mitochondria across the brain. Uh and uh

in the MSBY and the MD study were

linking this back to the the human

experience. And what's important to to

appreciate here is that information

flows not just from mitochondria out to

the cells, organs, individuals, and

communities, but also on the other uh

the other direction. And um which is

something we're we're carefully looking

at. In terms of future directions, there

are three particular areas that uh I'm

I'm excited that our lab is going to

make um efforts towards. First is using

principles of physics and bioenergetics

and energy expenditure to understand how

hyper metabolism contributes to

mitochondrial disease and how burning

energy faster shapes not only cells but

organ and and individual lifespan. And I

imagine that this could lead the way to

new uh approaches and interventions to

promote health before disease sets in

and perhaps therapeutics uh that could

target directly hyper metabolism if we

were to find that this is really a

causal link in the chain. And we have a

number of studies that will uh build the

basis for for this. Uh we still have a

ton to learn from our cellular lifespan

system uh including mechanisms of stress

and aging and how stress actually makes

its way inside the cell nucleus to shape

epigenetic and gene regulatory processes

as well as time perception. How do cells

and and people perceive time uh seem to

be uh intimately linked to to

mitochondrial processes. And I can

imagine that in a few years we'll be on

our way to the mitobrain map 2.0

uh and uh we'll draw inspiration and and

approaches from other fields maybe like

experimental psychology uh to test the

the boundaries and um and the spectrum

of the mind mitochondria connection.

Uh if we think about long-term vision uh

this is just a spot check on our master

plan. Uh I think we've made some

progress in developing tools and

approaches uh to quantify mitochondrial

health and signaling. Uh but that's

definitely something we'll continue

working on in the future.

uh we've uh started to identify and map

some mitochondrial psychobiology

mechanisms uh but definitely the bulk of

the work remains to be done for for that

step. Uh I think we've just started to

uh perform studies uh that will yield

clinically meaningful insights. So

that's very much in progress step. And

uh step four which is uh my dream to see

uh to see approaches uh spring up where

we can actually quantify health uh

before disease happens and we can

actually do something to promote health

before the onset of of disease. And I

imagine this is also going to include

importantly uh contributing to medical

training on brain body and mind

mitochondria processes uh as we learn

more and more how they relate to

processes of this u modifiable part p

part of the pie and mod modifiable

determinance of health. So in in closing

I'd like to acknowledge a few people

that have made particularly important

contributions. um Richard for bringing

me uh here at Colombia initially uh

Carolyn, Eugene, Dave, we share a floor

and um this is very important. Uh I

mentioned Mio, Phil, Stephanie, uh Serge

for also trusting me to join the the

program at Colombia which made

everything possible and Matt for being a

great friend over the past six years and

teaching me some important things about

uh medicine. and uh in particular Mitcho

mentioned he's allowed me into his uh

neuromuscular clinic on the Wednesday

morning and this just brings so much

meaning to to my uh professional life

and and to the the work that my lab

does. uh and I want to thank again uh

people who've contributed key pieces of

my training and uh have allowed me given

me the freedom as a PhD student to

explore different things and as a as a

postoc uh and people who help uh my

thinking uh around important issues that

reach widely across disciplines and

although Bruce is no longer with us uh

he continues to inspire me uh into how

to best train the next generation of

mitochondrial psychobiologist ologist.

Uh and and finally, I I think uh this is

maybe the most important slide. Uh a lot

of the work I showed would not have been

possible without fantastic collaborators

and I feel so fortunate to have had the

chance to interact with wonderful

scientists from across a number of

disciplines including mitochondrial

biology, psychosocial sciences, brain

neurobiology, neuro imaging, aging and

energy expenditure and metabolism. And I

I feel very excited uh that the the

mitochondrial psychobiology agenda has

spurred interest and and energy among

different fields and I think u it's an

exciting time. So again thank you so

much for this opportunity to share with

uh both my home departments of

psychiatry and neurology the work that

my lab has done. Um it's truly a

pleasure.

>> Martin uh e excellent lecture. Thank you

so much for for sharing your your

thoughts with us and your your amazing

work. Um I'm glad there's an explanation

for my premature gray hair despite being

in my mid20s. Um uh several people I

know have to get myself included have to

jump off the call, but if if there's

interest, maybe folks can stay on if

they have questions for you. Um and I'll

just let folks chime in uh when they do.

>> Thank you, Adam. Thank you.

>> Yes. Any questions?

>> Okay, Martin, I I'll start with one. Uh,

so you talk about mitochondrial sulfree

mitochondrial DNA as a hormone. So what

is a receptor and how's that

functioning?

>> Yeah, that's a great question, Mitch.

For something to be a hormone, there it

needs to be elicited by a stimulus. It

needs to be transported in some way and

there needs to be a receptor. So there's

a few potential candidate receptors for

mito cellfree mitochondrial DNA. uh but

we're still in in the early phase of I

think validating this idea that

mitochondrial DNA is a hormone and that

uh the current step is to understand how

it it's actually circulating and it

looks like it's not just naked little

piece of DNA that would be bound by

tolike receptors but most likely

embedded either inside whole

mitochondria or inside extracellular

vesicles. So um there might not be a

canotical extracellular receptors but it

might be that they get internalized and

and then affect target cells in a

different way than than you know classic

hormones do.

>> Following up on that I was just

wondering if it act like a transfection

like in viral infections of cells if you

isolate the DNA you can transact cells

without having a formal receptor. So I

was wondering if it would borrow

something like that mechanism and thank

you for a great talk. Yes, that's a

great point Carolyn and indeed I mean

every form of life uh you know has

exhibited the capacity for horizontal

gene transfer right so genes are being

transferred hor not through evolution uh

but horizontally you know within the

lifespan between cells uh conspecific

cells um so it's quite likely that there

are conserved mechanisms and that the

transfer of mitochondria and

mitochondrial DNA from cell to cell in

the living organism is actually a very

important part of uh a process for to

sustain help. So these at the moment is

mostly speculation and there's still a

lot of work to to do to uh test those

ideas.

>> Okay,

>> maybe I can just unmute myself. Martin,

this was really inspiring. Really,

really fantastic talk. I'm super

impressed. Wow. I have one quick

question regarding the selfie mitochond

DNA as well. He showed that the response

time at which he can pick up signals

changes in self-free medical DNA maybe

on the order of minutes.

>> I wonder about the relation and

implication of the technology that you

use in order to pick that up meaning the

sensitivity of your assay and what that

might mean for how much mitochond DNA is

being released into the bloodstream or

the saliva and so on. It seems like it

might be quite a lot or what do you

think?

>> Yes, I agree. So first part yes it moves

very quickly. Initially we were doing

everyday measurements thinking that you

know it's probably going to be a um a

trait like property. Some people have

higher levels some people have lower

levels. People that are sick might have

higher levels. And then we realized that

if you measure once a day you know

things move too much. It's too noisy.

Then we started to measure every hour.

And then we realized we're still not

capturing you know sampling fast enough.

And then based on the ny nyquist

sampling frequency we try to sample

every five minutes thinking clearly this

is going to be fast enough but I think

every five minutes is still not

capturing the true dynamics. uh so

practically not sure how how how well we

can go below five minutes but yes it's

extremely dynamic and I think we might

be at the place where um you know

measuring brain activity or or uh you

know EEG was I don't know 100 years ago

when people started to measure you know

brain activity realizing wow how dynamic

this is and that you needed millisecond

you know or submillisecond resolution so

we need subminute resolution maybe to

fully profile mitochondrial signaling in

humans uh which is really exciting and

and then also really puzzling. Um and we

can talk more, you know, offline about

the methods that we're using for for

doing this, but there's I think a great

opportunity there. Um and particularly

because we're seeing the signal being

consistent between different bofluids.

So that makes us particularly confident

that this is real signal.

I have a a question or a comment about

um well first of all a beautiful talk

it's amazing um about um like uh the

connection between bacterial conjugation

and this release of DNA and if the they

uptake if they uptake DNA um

if you can make a comment on that

>> yeah good question you know many of you

I think will know mitochondria used to

be bacteria about 1.5 billion years ago.

So they've preserved a lot of their

features as back from their bacterial

ancestors, the the double membrane, the

circular DNA, the ability to to fuse and

conjugate. U so I think quite likely

what we're seeing here is maybe a more

evolved form of of communication and

mitochondria have you know were probably

instrumental to uh the evol the

development of the multiorgan u you know

bodies that we enjoy now. uh and they've

learned to, you know, probably the

reason we have lungs and we have a heart

and a cardiovascular system is to bring

oxygen to mitochondria. Uh and if you

take that perspective, then most likely

mitochondria have learned also to to

harness the power of of a systemic

circulation to to talk to each other.

And and we have good evidence that there

are mitochondria in parts of the body

that are releasing signals that are

picked up by mitochondria in other parts

of the body. So we can start to see the

organism as a an interconnected uh

network of of different kinds of

mitochondria and and the cells and the

organs are there kind of to to sustain

them. So that's the extreme of a of the

mitoric perspective but maybe it's not

too far from the truth.

>> Yeah. Thanks.

>> Hi Martin, congratulations. I would like

to ask uh just one quick question. Maybe

I missed I was I'm sorry I just attended

your talk towards the end. Uh so is

there any modification in the

mitochondria which has been secreted? Is

it modified or it's just as plain

mitochondria as you know metilated

unmetilated or part of it?

>> Yeah, great question. Uh we don't know.

I think we're at the very beginning of

of this field of understanding what

those signals are and at the moment you

know with our tools are reductionists so

we're looking at specific you know

aspect of quantifying total

mitochondrial DNA. So I think what

you're pointing at is a next frontier in

understanding uh you know the nature of

the signal that's being released and and

then along with the the temporal

dynamics and and other factors that

might influence the information that's

being communicated. Mhm. So can't quite

So yeah, I think we're well over the

hour. So maybe uh Martin, we can uh ask

you to maybe answer questions by email

or phone uh for people who are maybe too

shy to ask right now.

>> That was fantastic.

>> Thank you so much. Thank you, Mitchio.

Thank you everyone for your attention.

Congratulations. Happy New Year. It's

great to