Regulation of autophagy by mitochondrial phospholipids in health and diseases

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Abstract

Autophagy is an evolutionarily conserved mechanism that maintains nutrient homeostasis by degrading protein aggregates and damaged organelles. Autophagy is reduced in aging, which is implicated in the pathogenesis of aging-related diseases, including cancers, obesity, type 2 diabetes, cardiovascular diseases, and neurodegenerative diseases. Mitochondria-derived phospholipids cardiolipin, phosphatidylethanolamine, and phosphatidylglycerol are critical throughout the autophagic process, from initiation and phagophore formation to elongation and fusion with endolysosomal vesicles. Cardiolipin is also required for mitochondrial fusion and fission, an important step in isolating dysfunctional mitochondria for mitophagy. Furthermore, genetic screen in yeast has identified a surprising role for cardiolipin in regulating lysosomal function. Phosphatidylethanolamine plays a pivotal role in supporting the autophagic process, including autophagosome elongation as part of lipidated Atg8/LC3. An emerging role for phosphatidylglycerol in AMPK and mTORC1 signaling as well as mitochondrial fission may provide the first glimpse into the function of phosphatidylglycerol apart from being a precursor for cardiolipin. This review examines the effects of manipulating phospholipids on autophagy and mitophagy in health and diseases, as well as current limitations in the field. This article is part of a Special Issue entitled: Lipids of Mitochondria edited by Guenther Daum.

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The role of Atg proteins in autophagosome formation.

Noboru Mizushima, Tamotsu Yoshimori, Yoshinori Ohsumi (2011)

Macroautophagy is mediated by a unique organelle, the autophagosome, which encloses a portion of cytoplasm for delivery to the lysosome. Autophagosome formation is dynamically regulated by starvation and other stresses and involves complicated membrane reorganization. Since the discovery of yeast Atg-related proteins, autophagosome formation has been dissected at the molecular level. In this review we describe the molecular mechanism of autophagosome formation with particular focus on the function of Atg proteins and the long-standing discussion regarding the origin of the autophagosome membrane.

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Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum

Elizabeth L. Axe, Simon A. Walker, Maria Manifava … (2008)

Autophagy is the engulfment of cytosol and organelles by double-membrane vesicles termed autophagosomes. Autophagosome formation is known to require phosphatidylinositol 3-phosphate (PI(3)P) and occurs near the endoplasmic reticulum (ER), but the exact mechanisms are unknown. We show that double FYVE domain–containing protein 1, a PI(3)P-binding protein with unusual localization on ER and Golgi membranes, translocates in response to amino acid starvation to a punctate compartment partially colocalized with autophagosomal proteins. Translocation is dependent on Vps34 and beclin function. Other PI(3)P-binding probes targeted to the ER show the same starvation-induced translocation that is dependent on PI(3)P formation and recognition. Live imaging experiments show that this punctate compartment forms near Vps34-containing vesicles, is in dynamic equilibrium with the ER, and provides a membrane platform for accumulation of autophagosomal proteins, expansion of autophagosomal membranes, and emergence of fully formed autophagosomes. This PI(3)P-enriched compartment may be involved in autophagosome biogenesis. Its dynamic relationship with the ER is consistent with the idea that the ER may provide important components for autophagosome formation.

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Autophagy maintains stemness by preventing senescence.

Laura García-Prat, Marta Martinez-Vicente, Eusebio Perdiguero … (2016)

During ageing, muscle stem-cell regenerative function declines. At advanced geriatric age, this decline is maximal owing to transition from a normal quiescence into an irreversible senescence state. How satellite cells maintain quiescence and avoid senescence until advanced age remains unknown. Here we report that basal autophagy is essential to maintain the stem-cell quiescent state in mice. Failure of autophagy in physiologically aged satellite cells or genetic impairment of autophagy in young cells causes entry into senescence by loss of proteostasis, increased mitochondrial dysfunction and oxidative stress, resulting in a decline in the function and number of satellite cells. Re-establishment of autophagy reverses senescence and restores regenerative functions in geriatric satellite cells. As autophagy also declines in human geriatric satellite cells, our findings reveal autophagy to be a decisive stem-cell-fate regulator, with implications for fostering muscle regeneration in sarcopenia.