Autophagy promotes longevity—except in the presence of ‘leaky’ mitochondria

Commentary on ‘Mitochondrial permeability uncouples elevated autophagy(definition) and lifespan extension’ by Zhou B. et al., Cell, 2019. Once humans abandoned their hunter ancestors’ roaming lifestyle and settled down in permanent dwellings, they realized the importance and significance of housekeeping. Ironically, our cells long preceded us to this realization as they developed their own miniature housekeeping mechanism, known as autophagy (Greek for ‘self-eating’). During this evolutionarily-conserved process, potentially toxic cellular waste, such as damaged, dysfunctional, or simply long-lived organelles and protein aggregates, are sequestrated and enzymatically degraded in order to maintain cellular homeostasis. Astonishingly, autophagy does not only serve as a detoxification tool but also supports cellular fitness by directing the resulting products from waste hydrolysis towards energy production and cellular recycling. By virtue of these fundamental respo-nsibilities, autophagy is considered a vital homeostatic process essential for life during both standard and stressful conditions alike.1 In fact, the reduction in autophagy observed in ageing is causally implicated in the age-associated functional decline of different organs. In support of this notion, boosting autophagy through transgenic, nutritional, or pharmacological means has been shown to robustly improve health, including within the cardiovascular system,2,3 and promote longevity in various organisms, including mammals.4 That being said, it is quite puzzling why in a particular subset of diseases, such as ischaemic heart disease and cancer, autophagy appears to be a double-edged sword that can, at times, cause more harm than good.5,6 In their recent study, Zhou et al.7 have significantly furthered our understanding of this conundrum as they convincingly attributed such paradoxical effects of autophagy to abnormalities in mitochondrial permeability. In detail, they found increased mitochondrial leakage in serum/glucocorticoid kinase 1 (sgk-1) mutated Caenorhabditis elegans to causally underlie their shortened lifespan, despite having increased autophagy. More importantly, the lifespan of these mutants could be restored to normal levels either through inhibition of autophagy or the lowering of mitochondrial permeability. Mechanistically, the authors reported that the loss of SGK1 increases mitochondrial permeability via facilitating the opening of the mitochondrial permeability transition pore (mPTP). In support of this idea, they found a direct interaction between SGK1 and an mPTP regulator known as voltage-dependent anion channel (VDAC). Indeed, through a series of experiments in which they genetically down-regulated VDAC levels or pharmacologically blocked mPTP opening, the authors could rescue the lifespan of these worms. This, thereby confirmed that VDAC-mediated mPTP opening is responsible for the increased mitochondrial permeability in sgk-1 mutants. The authors then proceeded to demonstrate that low mitochondrial permeability is a prerequisite for longevity promotion by caloric restriction(definition), the gold standard autophagy-boosting regimen, in eat-2 mutants. In fact, inducing mPTP opening through VDAC overexpression completely negated any lifespan-extending effect of caloric restriction in these mutants. Hence, the authors concluded that the presence of increased mitochondrial permeability abolishes the benefits of boosting autophagy, which in this scenario, represents a destructive force that exacerbates cellular dysfunction and shortens lifespan (Figure 1). Normal mitochondrial permeability is a prerequisite for lifespan extension by autophagy. Lack of the serum/glucocorticoid kinase 1 (SGK-1) causes mitochondrial permeability transition pore (mPTP) opening due to accumulation of voltage-dependent anion channel (VDAC). Increased mitochondrial permeability, in turn, leads to detrimental hyperactivation of autophagy and lifespan shortening. Contrarily, autophagy activation in the presence of normal mitochondrial permeability extends lifespan. This figure was created with BioRender.com. Normal mitochondrial permeability is a prerequisite for lifespan extension by autophagy. Lack of the serum/glucocorticoid kinase 1 (SGK-1) causes mitochondrial permeability transition pore (mPTP) opening due to accumulation of voltage-dependent anion channel (VDAC). Increased mitochondrial permeability, in turn, leads to detrimental hyperactivation of autophagy and lifespan shortening. Contrarily, autophagy activation in the presence of normal mitochondrial permeability extends lifespan. This figure was created with BioRender.com. Although these findings might argue for a possible link between mitochondrial permeability and ageing, the extent to which age-related structural changes in the mitochondria and mPTP affect their permeability is yet to be examined. Consequently, whether specific targeting of mitochondrial permeability per se is sufficient to delay natural ageing and promote longevity needs further examination. It should be noted, however, that if ageing was universally associated with excessive mitochondrial permeability, then all autophagy-inducing interventions tested would have been lifespan-shortening—which is not the case. In fact, an extensive body of evidence strongly supports autophagy induction as a lifespan-extending intervention.4,8 Therefore, it is reasonable to speculate that mitochondrial permeability might not be excessively compromised during the course of normal healthy ageing. Regardless, the findings of Zhou et al. have pivotal implications on various disease settings where mitochondrial permeability is known to be abnormally high, such as ischaemia–reperfusion injury.9 A major clinical entity of ischaemic and reperfusion injury is coronary artery disease, which remains a leading cause of morbidity and mortality worldwide, despite significant progress in myocardial revascularization interventions. One of the major known,