Mitochondria are power plants, hundreds of them in every cell. A mitochondrion is descended from symbiotic bacteria, essentially a wrapper around the electron transport chain, which is a complex system that produces either heat or molecules of adenosine triphosphate (ATP), a chemical energy store used to power the cell. It also produces reactive oxidative molecules as a side-effect of its energetic process of operation, which the cell treats as both a source of damage to be repaired and a signal to adjust operations. Improving mitochondrial function slows aging. Interesting, so does mild sabotage of the electron transport chain, causing the cell to react to the reduced supply of ATP and increased generation of oxidative molecules by increasing its maintenance and defense efforts - the benefits outweigh the harms. This is all very complex, however; any change cascades to produce second order effects, and it is hard to predict in advance whether a novel mitochondrially targeted intervention will be beneficial or harmful in aggregate. Once the results are demonstrated it is then hard to understand why it is beneficial or harmful.
Damage to mitochondrial DNA (mtDNA) results in defective electron transport system (ETS) complexes, initiating a cycle of impaired oxidative phosphorylation (OXPHOS), increased reactive oxygen species (ROS) production, and chronic low-grade inflammation (inflammaging). This culminates in energy failure, cellular senescence, and progressive tissue degeneration. Rapamycin and metformin are the most extensively studied longevity drugs. Rapamycin inhibits mTORC1, promoting mitophagy, enhancing mitochondrial biogenesis, and reducing inflammation. Metformin partially inhibits Complex I, lowering reverse electron transfer (RET)-induced ROS formation and activating AMPK to stimulate autophagy and mitochondrial turnover. Both compounds mimic caloric restriction, shift metabolism toward a catabolic state, and confer preclinical - and, in the case of metformin, clinical - longevity benefits.
More recently, small molecules directly targeting mitochondrial membranes and ETS components have emerged. Compounds such as Elamipretide, Sonlicromanol, SUL-138, and others modulate metabolism and mitochondrial function while exhibiting similarities to metformin and rapamycin, highlighting their potential in promoting longevity. The key question moving forward is whether these interventions should be applied chronically to sustain mitochondrial health or intermittently during episodes of stress. A pragmatic strategy may combine chronic metformin use with targeted mitochondrial therapies during acute physiological stress.
Link: https://doi.org/10.3390/biom15050614
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