During autophagy mitochondria elongate, are spared from degradation and sustain cell viability

Abstract

SummaryA plethora of cellular processes, including apoptosis, depend on regulated changes in mitochondrial shape and ultrastructure. Scarce is our understanding of the role of mitochondria and of their morphology during autophagy, a bulk degradation and recycling process of eukaryotic cells’ constituents. Here we show that mitochondrial morphology determines the cellular response to macroautophagy. When autophagy is triggered, mitochondria elongate in vitro and in vivo. Upon starvation cellular cAMP levels increase and protein kinase A (PKA) becomes activated. PKA in turn phosphorylates the pro-fission dynamin related protein 1 (DRP1) that is therefore retained in the cytoplasm, leading to unopposed mitochondrial fusion. Elongated mitochondria are spared from autophagic degradation, possess more cristae, increase dimerization and activity of ATP synthase, and maintain ATP production. When elongation is genetically or pharmacologically blocked, mitochondria conversely consume ATP, precipitating starvation-induced death. Thus, regulated changes in mitochondrial morphology determine the fate of the cell during autophagy.

The Eutherian Armcx genes regulate mitochondrial trafficking in neurons and interact with Miro and Trak2

“…5a,b). In agreement with previous studies [29][30][31] , we observed a constant increase in mitochondrial fusion events over time ( Supplementary Movies 2 and 3). The rate and dynamics of these events in cells transfected with Alex3 were identical to those in control cells ( Fig.…”

The mitochondrial phosphate carrier: Role in oxidative metabolism, calcium handling and mitochondrial disease

“…Although mitochondrial ATP production is an obvious major target of PiC deficiency, downstream effects of a limitation in mitochondrial ATP production may have their own consequences. In this regard, OPA1-mediated IMM fusion is sensitive to the level of oxidative phosphorylation (Mishra et al 2014), and mitochondrial fusion can function to acutely preserve ATP production in response to stress [71][72][73]. Thus the PiC should be crucial to the effectiveness of this stress response.…”

Quality control of mitochondria during aging: Is there a good and a bad side of mitochondrial dynamics?

“…More data on mitochondrial dynamics from non-tumor cell lines are needed Recent advances in this area however, enabled several studies on fusion and fission processes to be carried out using primary tissues [37,55]. In the latter study a mouse model expressing photo-activatable mito-Dendra-2 was generated that could help quantify mitochondrial dynamics in a gene-, tissue-, and age-dependent manner in vivo.…”

“…Aging hypothesis: Deceleration of fusionfission cycles improves mitochondrial quality control Microscopic investigations revealed that mitochondria are organized within a highly dynamic network that is governed by mitochondria undergoing cycles of fusion and fission that result in the mixing of their molecular content [28][29][30][31][32]. Mitochondrial dynamics and consequently changes in mitochondrial morphology are regulated at multiple levels including limited proteolysis, ubiquitinylation, phosphorylation, sumoylation, and disulfide formation of critical fusion and/or fission factors [20,[33][34][35][36][37][38][39][40][41][42][43][44].…”

“…In this way dysfunctional mitochondria become spatially separated from the intact network and, importantly, distinguishable from intact mitochondria. This is needed to prime them for their selective degradation by autophagy (mitophagy) and several reports have confirmed that mitochondrial fission is indeed required for the selective removal of mitochondria in mammals [37,38,[47][48][49][50]. Damaged mitochondria are subsequently marked by stabilization of PINK1 at the outer membrane and by recruitment of PARKIN [17,18] which represent early steps in mitophagy.…”