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Sorting nexins are a conserved protein family involved in vesicle transport, membrane trafficking and protein sorting. The sorting nexin ATG24/SNX4 has been demonstrated to be involved in different autophagy pathways and in endosomal trafficking. However, its impact on cellular quality control and on aging and development is still elusive. Here we report studies analyzing the function of PaATG24 in the aging model Podospora anserina. Ablation of PaATG24 leads to a reduced growth rate, infertility, and to a pronounced lifespan reduction. These characteristics are accompanied by alterations of the morphology and size distribution of vacuoles and severe impairments in non-selective and selective autophagy of peroxisomes (pexophagy) and mitochondria (mitophagy). While general autophagy and pexophagy are almost completely blocked, a PaATG24-independent form of mitophagy is induced during aging. In the ΔPaAtg24 mutant a strong accumulation of peroxisomes occurs while mitochondrial abundance is only slightly increased. These mitochondria are partially affected in function. Most strikingly, although some PaATG24-independent mitophagy exists, it appears that this is not sufficient to remove dysfunctional mitochondria efficiently enough to prevent premature aging. Overall our data emphasize the key role of mitochondria in aging and of mitophagy in quality control to keep a population of “healthy” mitochondria during aging.
Mitochondria are the "power plants" of eukaryotic cells involved cellular energy metabolism and lead the generation of most of the cellular "energy currency" adenosine triphosphate (ATP). In addition, they have other crucial functions including the control of programmed cell death, iron/sulfur cluster biogenesis and copper and calcium homeostasis. Mitochondrial dysfunction is deleterious and leads to degeneration, disease and aging. A number of individual pathways are active in keeping mitochondria functional over longer periods of time and thereby have a strong impact on lifespan. These mitochondrial quality control (mtQC) pathways occur at different molecular and cellular levels and are all limited in their capacity. They do not all work at the same time. Some of them are induced when others fail. Currently, the underlying molecular interaction of pathways and their regulation is only initially elucidated. ...