Abstract
Mitochondrial F1Fo-ATP-synthase dimers play a critical role in shaping and maintenance of mitochondrial ultrastructure. Previous studies have revealed that ablation of the F1Fo-ATP-synthase assembly factor PaATPE of the ascomycete Podospora anserina strongly affects cristae formation, increases hydrogen peroxide levels, impairs mitochondrial function and leads to premature cell death. In the present study, we investigated the underlying mechanistic basis. Compared to the wild type, we observed a slight increase in non-selective and a pronounced increase in mitophagy, the selective vacuolar degradation of mitochondria. This effect depends on the availability of functional cyclophilin D (PaCYPD), the regulator of the mitochondrial permeability transition pore (mPTP). Simultaneous deletion of PaAtpe and PaAtg1, encoding a key component of the autophagy machinery or of PaCypD, led to a reduction of mitophagy and a partial restoration of the wild-type specific lifespan. The same effect was observed in the PaAtpe deletion strain after inhibition of PaCYPD by its specific inhibitor, cyclosporin A. Overall, our data identify autophagy-dependent cell death (ADCD) as part of the cellular response to impaired F1Fo-ATP-synthase dimerization, and emphasize the crucial role of functional mitochondria in aging.
Highlights
LeeuwenburghBiological aging is a process that is characterized by a time-dependent decrease in physiological functions and an increase in morbidity and mortality of biological systems.It is controlled by environmental, stochastic and genetic traits
PaMCA2, apoptosis inducing factors (AIFs), poly (ADP-ribose) polymerase (PARP), cyclophilin D (CYPD) and apoptotic or type I programmed cell death (PCD) has been identified as the underlying mechanism [20,61,62,63,64]
Cell death may occur via the excessive induction of autophagy leading to type II PCD or autophagy-dependent cell death (ADCD)
Summary
LeeuwenburghBiological aging is a process that is characterized by a time-dependent decrease in physiological functions and an increase in morbidity and mortality of biological systems.It is controlled by environmental, stochastic and genetic traits. Biological aging is a process that is characterized by a time-dependent decrease in physiological functions and an increase in morbidity and mortality of biological systems. Mitochondria have been demonstrated to play a paramount role in aging [1,2,3,4,5,6,7,8]. These organelles are involved in different important cellular processes including energy transduction, iron–sulfur cluster biosynthesis, and programmed cell death (PCD). A network of pathways involved in maintenance of a “healthy” population of mitochondria is effective and counteracts the time-dependent accumulation of functionally impaired mitochondria [9].
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