Mitochondria and aging

Mitochondria and aging Mitochondria have been closely examined in aging because of their roles in cellular energy production, calcium homeostasis, apoptosis, and cell signaling (1). For example, mitochondrial dysfunction is linked to metabolic and oxidative damage pathology in Alzheimer’s disease and Parkinson’s disease (2–5). This is not entirely surprising because the brain is one of the most mitochondria-rich tissues and is particularly sensitive to changes in mitochondrial function. Similarly, mitochondrial dysfunction is also linked to diabetes and obesity. Recent research suggests that this dysfunction may even be causative (6–8). Likewise, mitochondrial dysfunction and mitochondrial DNA instability are highly associated with cancer (9–11). In many cancers, a phenomenon called the Warburg effect, in which these cancerous cells switch to glycolysis over oxidative respiration, has been observed (12). Several aspects of mitochondrial dysfunction — such as mitochondrial DNA (mtDNA) mutations, nuclear DNA mutations that encode mitochondrial proteins, mitochondrial copy number, and morphological dynamics (i.e., fusion and fission) — have been studied in aging. First, mitochondria do not possess comparable DNA repair mechanisms to those found in the nucleus. Their inefficient repair mechanism combined with the proximity of the mtDNA to the electron transport chain — which generates a large amount of reactive oxygen species — promotes a high number of mtDNA mutations over a lifetime. Excessive mtDNA mutations cause an aging phenotype, as demonstrated in POLG mutator mice, which have early sarcopenia, hair graying and loss, abnormal body composition, reduced fertility, and reduced lifespan (13–15). Additional studies in worms, flies, and mice suggested that manipulating mitochondria and mitochondrial genes could increase lifespan across species (16–19). For example, increased lifespan by anywhere from 15% to 30% depending on the genetic background is observed following reduction of the gene encoding the mitochondrial enzyme CLK-1, which is required for proper mitochondrial function (clk-1 in worms, or Mclk1 in mice) (17, 20, 21). Yet exactly how this increase in lifespan is dependent on mitochondrial mechanisms remains unclear (22, 23). Furthermore, mitochondrial copy number, the relative ratio of mtDNA compared with nuclear DNA, has been connected to aging. In humans, low mitochondrial copy number in peripheral blood cells is associated with poorer cognitive functioning and higher all-cause mortality (24). However, these results should be interpreted with caution. It is unclear whether changes in mitochondrial copy number in, for example, brain regions and brain cell types absolutely affect cognition. To robustly estimate the effects of mitochondrial copy number on cognitive function requires great statistical power in the form of sufficient sample size, cell dissociation, and deep phenotypic characterization. However, a recent report did implement whole-genome sequencing on 1361 human brain samples and highlighted that Alzheimer’s disease patients showed low mitochondrial copy number (25). Determining whether neuronal or glial mitochondrial copy number is driving these effects, and improving mtDNA-specific next-generation sequence analysis, are excellent objectives worth addressing in future research. The latest research has suggested the usefulness of machine learning–based approaches to improve quantification of mtDNA copy number and low-frequency variants to estimate heteroplasmy (26). Moreover, the roles of mitochondrial morphological dynamics in aging continue to be explored, but many questions remain unanswered. Still, inhibition of fission in Saccharomyces cerevisiae resulted in accelerated death, an effect that was also seen in Caenorhabditis elegans and Drosophila melanogaster (27–29). Additionally, mice under calorie restriction not only lived longer but also showed increased mitochondrial length in muscle fibers (30). Likewise, in human postmortem brain samples with Alzheimer’s disease, the mitochondrial fusion proteins OPA1, MFN1, and MFN2 were significantly reduced, and levels of the mitochondrial fission protein FIS1 were significantly elevated (31). Taken together, these findings suggest that mitochondria are central to many age-related diseases and perhaps to the fundamental aging process. The mechanisms that explain mitochondrial dysfunction in aging and healthspan continue to be studied, but one element has been unexplored: microproteins. Small open reading frames in circular mitochondria DNA can encode multiple microproteins, called mitochondria-derived peptides (MDPs). Currently, eight MDPs have been published: humanin, MOTS-c, and SHLPs 1–6. This Review describes recent advances in microprotein discovery with a focus on MDPs. It discusses what is currently known about MDPs in aging and how this new understanding could add to the way we understand age-related diseases including type 2 diabetes, cancer, and neurodegenerative diseases at the genomic, proteomic, and drug-development levels. Mitochondria-derived peptides in aging and healthspan