Mitochondrial Dysfunction

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Hallmarks of Aging Miniseries No. 5


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As cells age, their mitochondria start to lose their integrity due to the build-up of oxidative stress. Compromised mitochondrial function leads to a number of events, such as increased apoptosis induction, that correlate with aging.

Not only are mitochondria responsible for generating ATP, but they act as sensors of cellular distress, and are the first parts of the cell to send and respond to cell death signals. Since the 2013 publication of The Hallmarks of Aging, the role of mitochondria in regulating inflammation in response to metabolic change (via mitochondrial sirtuins) has received greater attention.

Mitochondria send signals via calcium signaling and reactive oxygen species (ROS) to the NF-κB pathway, as well as via damage-associated molecular patterns (DAMPs) to the inflammasome, to activate “inflammaging.” In turn, proinflammatory molecules regulate mitochondria by causing decreases in mitochondrial membrane potential, a sign of poor cell health.

Melatonin signaling, on the other hand, affects the mitochondria positively, maintaining the integrity and function of these organelles. Melatonin decreases inflammation and maintains the efficiency of electron transport. Because of these powerful effects, maintaining melatonin levels via pharmaceuticals or by circadian regulation is an area of therapeutic interest. The future of mitochondrial dysfunction research will certainly include more genetic and epigenetic data around mtDNA, as well as their implications for innate immunity.



Mitochondrial dysfunction caused by aging
Mitochondrial dysfunction caused by aging-related insults can direct chronic inflammation mediated by the inflammasome, which is a multiprotein complex that includes NLRP3 and ASC.

Adapted from Misawa T, Takahama M, Kozaki T, Lee H, Zou J, Saitoh T, Akira S. Microtubuledriven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasome. Nat Immunol. 2013; 14(5):454-60. (Click image to enlarge)

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Did you know?
Approximately 3,000 genes are needed to make a mitochondrion. Of these, mitochondrial DNA (mtDNA) encodes 37 genes, and the remaining are from nuclear DNA (nDNA).
We are a lot like our cells ... 
Just like our cells find ways to reduce mitochondrial stress, as we age, we find ourselves finding ways to reduce stress and feel more at peace. Melatonin can help aging mitochondria cope with stress - and melatonin helps our entire bodies deal with life's stressors as well. A little bit of sunshine goes a long way.

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