Can we feel our mitochondria?

We feel pain (nociception), internal sensations (interoception), and even our immune system (immunoception)

How does the brain monitor our energy status?

In this preprint, we propose that the brain feels the balance of energy demand (burn rate) and energy transformation capacity (mitochondrial OxPhos capacity) via mitoception

Cellular studies, animal models, clinical, and human studies suggest that the cytokine GDF15 is the main signal of mitoception

Preprint by Cynthia Liu and colleagues
@torwager @LFeldmanBarrett @Danbelsky @Dr_Epel @cohenaginglab

osf.io/preprints/osf/…
Comments welcome! Every tissue expresses GDF15 at some level, whereas the receptor is only or mostly at appreciable levels in the brainstem

Perfect for body-to-brain signaling

Since we discovered that hair greying is reversible, we've received hundreds of testimonials and pictures showing white hairs regaining pigmentation

Head, beard, and pubic (!) hairs all showed reversibility of greying, revealing malleability for an hallmark of human aging

🧵 Latest example of a hair completely depigmented (grey) returning to its youthful dark color after over a year

The wet, carbon-based matrix of biology behaves like an electrical circuit, slowly fluxing electrons from food ⊖ → ⊕ oxygen

Through each step, energy flow meets energy resistance: éR

éR is the fire of life, allowing transformation and adaptation

Preprint here with the amazing Nirosha Murugan @msahsorin : osf.io/preprints/osf/…

Comments welcome!
Thanks to @drmichaellevin and others for commenting and helping improving the model In physical/mechanical systems, excessive resistance and dissipative loss drive information loss

In biological systems, the Energy Resistance Principle (ERP) predicts that elevated energy resistance (éR) is similarly the main driver of the cellular hallmarks of aging and disease

Social connections are key to health

But how do experiences materialize into biological processes linked to health and disease risk?

Across >42,000 people, the best protein biomarker of isolation/loneliness was the energetic stress marker GDF15

🧵
nature.com/articles/s4156… There are many more UPregulated than DOWNregulated proteins associated with loneliness

Making and secreting proteins costs energy

Loneliness doesn't "quiet down" the body, it accelerates processes and signaling, including the energetically costly secretion of blood proteins

Mitochondria are transferred between cells, tissues and organs, particularly in response to stressors

New exciting layer of mitochondrial biology showing the importance of cell-cell interactions and that mitochondria convey information/signal widely



🧵 nature.com/articles/s4225… Multiple mechanisms allow cells to share mitochondria

There are possibly some tissues and cell types that preferentially act as mitochondrial "donors", whereas other tissues may be better "acceptors"

During evolution, pieces of mitochondrial genome have been integrated in the nuclear genome

We now find that this process happens in the human brain across the lifespan and in cultured cells

journals.plos.org/plosbiology/ar… Of all metabolic, chemical, and possibly other ways in which mitochondria influence cellular functions and behaviors, changing the sequence of the nuclear genome may be one of the most "stable" mark

doi.org/10.1016/j.cmet…

How much energy do cells and organisms with impaired mitochondrial OxPhos waste in mounting (futile) stress responses?

Could hypermetabolism - rather than ATP deficiency - cause symptoms and disability in mitochondrial diseases?

nature.com/articles/s4225…
This hypermetabolism/energy constraint model contrasts with the central dogma model of ATP deficiency as the driver of disease.

To our knowledge, there is little evidence in vivo that ATP level actually dip in tissues of patients with mitochondrial diseases.

How much energy do we waste by generating psychobiological stress responses? And does this accelerate biological aging?

In human cultured fibroblasts, chronic stress increases the energetic cost by 60% of life and accelerate multiple aging biomarkers.

https://t.co/J3X5rQv5ROdoi.org/10.1016/j.psyn…
This matters because in humans, chronic stress results in "allostatic load", a dysregulated state associated with functional decline and increased mortality. @n_bobba_alves and @sturm_gav wanted to understand the cellular basis of this phenomenon with @Dr_Epel and colleagues

How we think and talk about mitochondria matters to our science and to newcomers in the field.

The powerhouse analogy is expired and we need specific vocabulary to capture the beautiful complexity of mitochondrial biology.

We propose a framework and some nomenclature. First thing to recognize is that we tend to look at mitochondria (and most things) with a narrow perspective often blind to the whole, leading to correct but limited observations about parts of the system. We need more integrative perspectives.

How much energy does stress cost to the human body-mind unit? Could the energetic cost of stress contribute to the damaging effects of chronic psychosocial stress on health and aging?
sciencedirect.com/science/articl… Human stress research was moved forward tremendously by the allostatic load model of chronic stress by Bruce McEwen, building on the concept of allostasis by @whatishealth21.

Allostasis, allostatic load, and allostatic overload cost energy above the basal cost of life.