Fight Aging!

Mitochondria are the power plants of the cell, producing the chemical energy store molecule adenosine triphosphate (ATP). Every cell contains hundreds of mitochondria, evolved from the symbiotic bacteria that took up residence inside the ancestors of today's eukaryotes. Mitochondria replicate like bacteria, can fuse together or pass around component parts, while damaged mitochondria are culled by mitophagy, a quality control mechanism. Mitochondrial function declines with aging, and this is associated with reduced mitophagy and changes in mitochondrial dynamics. This is an area of active and extensive study, but a complete and concrete understanding of how and why mitochondria become less effective in the cells of old tissues remains to be established.

A number of projects have focused on improving the efficiency of mitophagy in order to slow the age-related decline in mitochondrial function. How exactly the various drugs and supplements used in these programs act to improve mitophagy is largely understood only in outline, if at all. Some drugs are discovered by screening, and their mechanism of action only uncovered later. Others are developed to target a particular mechanism, but a full understanding of why that mechanism is important is only later established. As noted in today's open access paper, another approach is to try to alter mitochondrial dynamics in favorable ways, adjusting the pace of fission or fusion of mitochondria to alter average size or other structural and functional aspects. Mitophagy and mitochondrial dynamics are clearly closely connected, but again, a full understanding of why this is the case remains a work in progress.

Tuning mitochondrial dynamics for aging intervention

The mitochondrion is a double membrane structure within the cytoplasm that contains its own genome and generates the majority of the cell's energy via aerobic respiration. Mitochondria naturally eliminate pathogenic mitochondrial DNA (mtDNA) mutations and repair dynamic architectures by controlling organelle division and fusion via guanosine triphosphatase (GTPase) dependent signaling. In this process, fusion compensates partially damaged mitochondria, whereas fission generates new mitochondria and dilutes the fraction that is dysfunctional. It is known that defects in GTPase-driven biogenesis cause dysfunctional oxidative phosphorylation and this is associated with mammalian aging and organ failure. Therefore, effectively targeting mitochondrial quality has the potential to rejuvenate cellular biology and ameliorate aging-associated disease.

The GTPases Mitofusins 1 and 2 (MFN1 and MFN2) represent important targets in mitochondrial disease as they initiate mitochondrial membrane fusion. Indeed, a hallmark of myocardial aging is the accumulation of dysfunctional mitochondria due to non-redundant functions of MFN1 and 2. To target MFN1 fusion activity, a small molecule agonist was recently developed. Termed S89, it rescued mitochondrial fragmentation and swelling following ischemia/reperfusion injury by interacting with the GTPase domain of MFN1, thus delayed aging-derived senescence resulting from mitochondrial DNA mutations. To modulate MFN2's fusogenic activity, a further peptidomimetic small molecule, MASM7, was recently discovered. MASM7 activates MFN2 pro-tethering conformation and enables mitochondrial fusion resulting in increased membrane potential, mitochondrial respiration, and subsequent ATP production, providing promise to reduce age-related degenerative metabolic disease.

The regulation of mitochondrial fission in human aging has also been studied. The GTPase dynamin-related protein 1 (Drp1) uniquely triggers mitochondrial fission by chemoenzymatically constricting the mitochondrial surface to divide the organelle leading to mitophagy. Uncontrollable Drp1 activation leads to hyper-fragmentation, sustained opening of mitochondrial permeability transition pores and eventually apoptosis, which is commonly detected during aging. The most successful Drp1 inhibitor is Mdivi-1, a derivative of quinazolinone, which has been widely reported to mitigate disease, from myocardial failure to abnormal neurodegeneration. Most recently, a new covalent molecule named MIDI was discovered. MIDI interacts with Drp1 cysteines and effectively blocks Drp1 recruitment instead of directly targeting its tetramerization and GTPase activity. This provides a fresh angle to further establish Drp1 inhibitors that target age-related diseases.