Mitochondria, the power plants of the cell, are implicated as a cause of degenerative aging. Each cell has a herd of mitochondria, dividing like bacteria (mitochondrial biogenesis) and removed by quality control mechanisms when damaged (mitophagy). In an increasing number of cells with advancing age, all mitochondria are damaged, however, fallen into a state that slips past quality control and quickly overtakes the mitochondrial population. This appears to be a fairly rapid transition for an individual cell, but otherwise a rare event. Still, this growing population of dysfunctional cells causes significant harm, such as by exporting reactive molecules that damage lipids and contribute to atherosclerosis.
There are numerous schools of thought on how best to fix this problem, even if very few researchers are actually working on it - the usual state of affairs for anything likely to prove effective in the treatment of aging, sad to say. Gene therapies to deliver replacements for damaged mitochondrial genes, or drug treatments to provide a regular delivery of the proteins those genes produce, for example. Some researchers consider it worth looking into enhanced quality control, or otherwise tinkering with mitochondrial dynamics, but this seems like a comparative poor approach, likely to just slow things down rather than reverse the damage.
Maintenance of mitochondrial function and energy homeostasis requires both generation of newly synthesized and elimination of dysfunctional mitochondria. Impaired mitochondrial function and excessive mitochondrial content are major characteristics of ageing and several human pathophysiological conditions, highlighting the pivotal role of the coordination between mitochondrial biogenesis and mitophagy. However, the cellular and molecular underpinnings of mitochondrial mass homeostasis remain obscure.
In our recent study, we demonstrate that DCT-1, the Caenorhabditis elegans homolog of mammalian BNIP3 and BNIP3L/NIX, is a key mediator of mitophagy promoting longevity under stress. DCT-1 acts downstream of the PINK-1-PDR-1/Parkin pathway and is ubiquitinated upon mitophagy-inducing conditions to mediate the removal of damaged mitochondria. Accumulation of damaged mitochondria triggers SKN-1 activation, which initiates a bipartite retrograde signaling pathway stimulating the coordinated induction of both mitochondrial biogenesis and mitophagy genes.
Taken together, our results unravel a homeostatic feedback loop that allows cells to adjust their mitochondrial population in response to environmental and intracellular cues. Age-dependent decline of mitophagy both inhibits removal of dysfunctional or superfluous mitochondria and impairs mitochondrial biogenesis resulting in progressive mitochondrial accretion and consequently, deterioration of cell function.