for - adjacency - mitochondria - good dietary fats

adjacency - between - mitochondria health - good dietary fats - adjacency relationship - good dietary fats are essential to good mitochondria health because mitochondria are made of fats and require essential fatty acids as building blocks

for - question - health - insulin resistance - why aren't mitochondria within cells not responding to insulin?

question - health - insulin resistance - why aren't mitochondria within cells not responding to insulin? - The fat cells are being stored in the liver, resulting in - fatty liver disease - The liver stores the fat cells floating in blood (triglycerides) then recirculates it back to the cells. - The cells and liver are caught up in a vicious cycle of "hot potatos" with the fat cells.<br /> - (See Stanford explainer video above)

for - key insight - insulin covers up the real problem of mitochondria dysfunction

for - personal health - metabolic disease - insulin resistance caused by mitochondria dysfunction - interview - Dr. Robert Lustig - health - dangers of sugar in our diet

summary - Robert Lustig is a researcher and major proponent for educating the dangers of sugar as the root cause of the majority of preventable western disease - He explains how sugar and carbs are a major variable and root cause of a majority of these diseases - It is useful to look at these bodily dysfunctions from the perspective of Michael Levin, in which all these diseases of the body are problems with lower levels of the multi-scale competency architecture - https://jonudell.info/h/facet/?max=100&expanded=true&user=stopresetgo&exactTagSearch=true&any=michael+levin%2C+multi-scale+competency+architecture

for - health - insulin resistance - a symptom of mitochondria dysfunction

Review coordinated by Life Science Editors Foundation

Reviewed by: Dr. Angela Andersen, Life Science Editors Foundation

Potential Conflicts of Interest: None

Punch line: Activation of the yeast AMP-activated protein kinase (AMPK) negatively regulates MAGIC, inhibits the import of misfolded proteins into mitochondria & promotes mitochondrial biogenesis and fitness.

Why is this interesting? Maybe all those healthy things like caloric restriction, intermittent fasting, exercise etc that activate AMPK & extend lifespan do so by inhibiting MAGIC & preventing mitochondrial damage from misfolded proteins.

Background: Metabolic imbalance & loss of proteostasis are interconnected hallmarks of aging and age-related diseases. A mitochondria-mediated proteostasis mechanism called MAGIC (mitochondria as guardian in cytosol) concentrates cytosolic misfolded protein at the surface of mitochondria, where they are disaggregated by molecular chaperones, and then imported for degradation by mitochondrial proteases. Inhibition of this pathway prolongs protein aggregation in cytosol after proteotoxic stress, but excessive misfolded proteins in mitochondria can lead to mitochondrial damage.

Results: • Genetic screen for MAGIC regulators uncovered 145 genes. Loss of Snf1 (AMPK homolog) led to increased mitochondrial import even without proteotoxic stress. In contrast indirect, constitutive activation of Snf1 (e.g. low glucose) prevented the import of misfolded proteins in mitochondria.

• The data suggest that the reduced accumulation of misfolded proteins in mitochondria of Snf1-active cells is not due to enhanced intramitochondrial degradation nor to reduced levels of the misfolded protein, but rather due to blocked mitochondrial import.

• Deletion of HAP4 counteracted Snf1 activation and overexpression of Hap4 alone recapitulated Snf1 activation. The Hap2/3/4/5 complex activates the expression of nuclear encoded mitochondrial proteins. Their data suggest that high expression of mitochondrial preproteins due to an elevated Snf1-Hap4 axis compete with misfolded proteins for mitochondrial import.

• Proteotoxic stress led to a reduced growth rate & reduced mitochondrial fitness in high glucose medium but not under glucose limitation. The data suggest that low glucose, activation of Snf1 & prevention of misfolded protein import into mitochondria prevent the growth defect.

• Many neurodegenerative disease-associated aggregation-prone proteins (α-synuclein, FUSP525L, TDP-43, amyloid beta, C9ORF72-associated poly(GR) dipeptide) are detected in mitochondria of human patients or disease models and impair mitochondrial functions. Their data suggest that the import of α-synuclein & associated reduction in mitochondrial fitness can be counteracted by indirect AMPK/Snf1 activation (i.e. glucose limitation).

• Show data in yeast & human cells.

Discussion: This paper revealed an unexpected link between cellular metabolism and proteostasis through MAGIC/mitochondria.

• Snf1/AMPK is a key regulator of MAGIC & of misfolded protein import into mitochondria.

• Snf1/AMPK balances the mitochondrial metabolic and proteostatic functions in response to glucose availability and protects mitochondrial fitness under proteotoxic stress.

• The authors speculate that in high glucose, cells rely on glycolysis for ATP production and mitochondria ‘moonlighting’ in cellular proteostasis through MAGIC, but when glucose is limited and cells rely on oxidative phosphorylation for ATP generation, AMPK is activated and shuts down MAGIC, prioritizing the import of essential mitochondrial preproteins to ensure mitochondrial fitness and energy production.

• Acknowledge limitations: Snf1/Hap4 activation elevates the expression of hundreds of mitochondrial preproteins, not clear whether specific preproteins or cytosolic factors directly involved in inhibiting mitochondrial import, & that more details on mechanisms will be of interest.

• Caloric restriction & AMPK activation might contribute to lifespan extension by inhibiting MAGIC. In human, AMPK activity is elevated during health-benefitting activities such as exercise. Their data suggest that elevating AMPK activity may be beneficial in alleviating proteotoxicity associated with degenerative diseases - but hyperactivated AMPK has also been reported in several neurodegenerative diseases with proteostasis decline (Ang wonders- maybe AMPK is overwhelmed?).

THIS IS A GORGEOUS PAPER!

Future work - I can't wait to see the characterization of the ribosome biogenesis genes that they also pulled out as MAGIC regulators. Anticipating a translation, misfolded protein, mitochondria, aging axis :)

Review coordinated by Life Science Editors.

Reviewed by: Dr. Angela Andersen, Life Science Editors

Potential Conflicts of Interest: None

Background: The ability to reproduce decreases with age in many animals - including humans and worms. Oocytes age earlier than other tissues, and their decline in quality contributes to reduced reproduction. Diminished mitochondria number/activity in human oocytes correlates with age-related decline.

Question: Does mitochondrial dysfunction cause (or just correlate with) reduced egg quality?

Summary: The authors compared the proteomes of mitochondria isolated from young worms, old worms and daf-2 mutant worms (c. elegans) (insulin/igf-1 receptor mutant) that have longer lifespans & longer reproductive lifespan. * Mitochondria from young & mutant worms had high levels of BCAT-1 (branched chain aminotransferase). * RNAi of bcat-1 reduced the longevity, reproductive longevity & egg quality of daf2 mutants, and increased mitochondrial activity/mtROS. * Similar effects of bcat-1 kd in wt worms, but interestingly the effects on reproductive longevity were more severe in wt than daf2 mutants (from a quick look), but there was no effect on lifespan in wt animals. * Overexpressing bcat-1 in wt extended reproduction & egg quality but not lifespan. * Treating animals with vitamin B1 (a cofactor downstream of BCAT1 in BCAA metabolism) delayed reproductive aging, slightly extended lifespan, improved oocyte quality, reduced mtROS in aged worms..

Advance: BCAT-1 levels/BCAA metabolism correlate with mitochondrial quality & reproductive longevity. Vit B1, which promotes BCAA metabolism, can extended reproductive longevity.

Significance: More/strong evidence that dysfunctional mitochondria cause a decline oocyte quality, reduce reproductive longevity. If vitamin B1 supplements are a safe way to delay age-related decline of eggs in female mammals (humans) that would be amazing. .

Ang asks:

• is this effectively dietary restriction of BCAA? Would that be a better (albeit perhaps more difficult to sustain) approach?

• How does this relate to some recent papers pointing out that mitochondria in eggs are special (e.g. Cheng et al. Mammalian oocytes store mRNAs in a mitochondria-associated membraneless compartment, Science 2022; Rodriguez-Nuevo et al., Oocytes maintain ROS-free mitochondrial metabolism by suppressing complex I, Nature 2022) and a role for BCAA in longevity (e.g. Richardson et al., Lifelong restriction of dietary branched-chain amino acids has sex-specific benefits for frailty and life span in mice, Nature Aging 2021).

• How does low BCAA metabolism lead to mitochondrial dysfunction/oocyte aging? Is it related to accumulation of amino acids in the cytosol and toxicity to mitochondria? (e.g. Hughes et al., Cysteine toxicity drives age-related mitochondrial decline by altering iron homeostasis, Cell 2020).

• Overall these data support the idea that oocytes are particularly vulnerable to conditions that drive aging, and conserved aging mechanisms in the soma and germline as well as across species.

Within this human body, we embed 4 different stages of Major Evolutionary Transitions (MET).

Our human body is the product of billions of years of evolution, embodying various outputs from each major stage of a Major Evolutionary Transition (MET). We are a multi-cellular being, a colony. Yet,at the same time, we have living elements that at one time in history, were independent living beings which were NOT part of a multi-cellular colony!

In the deep history of the evolution of the human body, genes, mitochondria, eukaryotes were all once autonomous living entities, each a biological self with its own boundary separating inner from outer. Virus's helped to catalyze their mutualism over deep time.

Now, over billions of years of evolution, they are all integrated together by the extra-cellular matrix and laminin protein into our multi-cellular human body, replicating as one super, super, super organism.

Finally, inscribed language has allowed us to undergo another kind of transition, a major system transition (MST) where human beings now dominate the entire biosphere, for better and for worse.

Check out the peer review report for this article: http://www.plantcell.org/content/plantcell/suppl/2019/07/13/tpc.19.00033.DC2/tpc19.00033.PRR-Niittyla.pdf

So, this entire pathway, or segment, is dependent on mitochondria

All of the above is great info and there are many suspects, the main current is PPARgamma. TheNrf pathways hold quite a bit of niftiness in the translation regulation, cap dependent, independent proteins and folding. Seeking some connection to, causative agent to the age related and stress related cascade hinges on mitochodria in some, (it certainly has its finger in the pie-- but so do many root level processes) Part of my diligence in the mito domain is the Anti-Streetlight effect. That is, we have looked everywhere else and, yes, tehre are constantly new revelations, but these areas of mitochondria gentics, translational regulation and defects(both-not all "errors" are errors), and ribosomal and tRNA changes have been excluded from research and thought to be mechanistis and stable non-changing variables.And now, that they are known to be ariable...muchwill have to be reevaluated

Danism: A cell in a diseased state does not respond the same way as a cell in a non-diseased state. This is essential and has many roots. Translation Regulation being the most controversial.

keep track of this sulfur molecule. It has turned up in other areas.

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