The Mitochondrial Dynamism-Mitophagy-Cell Death Interactome

Abstract

Mitochondrial research is experiencing a renaissance in part due to the recognition that these endosymbiotic descendants of primordial protobacteria appear to be pursuing their own biological agendas. Not only is mitochondrial metabolism required to produce most of the biochemical energy that supports their eukaryotic hosts (us), but mitochondria can actively (through apoptosis and programmed necrosis) or passively (through reactive oxygen species toxicity) drive cellular dysfunction or demise. The cellular mitochondrial collective autoregulates its population through biogenic renewal and mitophagic culling; mitochondrial fission and fusion, two components of mitochondrial dynamism, are increasingly recognized as playing central roles as orchestrators of these processes. Mitochondrial dynamism is rare in striated muscle cells, so cardiac-specific genetic manipulation of mitochondrial fission and fusion factors has proven useful for revealing non-canonical functions of mitochondrial dynamics proteins. Here, we review newly described functions of mitochondrial fusion/fission proteins in cardiac mitochondrial quality control, cell death, calcium signaling, and cardiac development. A mechanistic conceptual paradigm is proposed in which cell death and selective organelle culling are not distinct processes, but are components of a unified and integrated quality control mechanism that exerts different effects when invoked to different degrees, depending upon pathophysiological context. This offers a plausible explanation for seemingly paradoxical expression of mitochondrial dynamism and death factors in cardiomyocytes wherein mitochondrial morphometric remodeling does not normally occur and the ability to recover from cell suicide is severely limited.

Downregulation of the PHLDA1 gene in IMR-32 neuroblastoma cells increases levels of Aurora A, TRKB and affects proteins involved in apoptosis and autophagy pathways

“…Pathways of molecular cross talk between apoptosis, programmed necrosis, and mitochondrial autophagy (mitophagy) signaling have recently been advanced by Dorn and Kitsis. They postulate that these processes are 'components of a unified and integrated quality control mechanism' (20). Encouraged by the aforementioned accounts, we sought to determine how PHLDA1 is interlinked to both apoptosis and autophagy pathways in our model.…”

Introductory Chapter: Overview on Autophagy in Burden of Functions

“…Note the phagophore formation is mediated by the Atg12-Atg5-Atg16L and LC3/GABARAP/Atg8-phosphatidylethanolamine autophagy conjugates produced via activation of two ubiquitin-like enzymes E1 and E2 (i.e., Atg7 and Atg10-for Atg12 conjugation system and Atg7 and Atg3-for Atg8 conjugation system), and is assisted by an autophagosome-specific pool of phosphatidylinositol-3-phosphate and syntaxin-17 [1,5,13, current book Chpts. 2,6,12,16,21]. These observations are crucial for understanding efficacy of the macroautophagy target-sequestration from topological perspective.…”

“…In conjunction with this, interestingly that "membrane structural modules" arranged by mitochondria and endoplasmic reticulum (or the ER-mitochondrial axes), which are other key players in cell bioenergetics and proteostasis, are also involved in the emerging macroautophagy signaling mechanisms [5,6,12,13]. Thus, numerous reports indicate that the ER-mitochondrial membrane modules along with their contact membranes (i.e., mitochondria-associated membranes -MAMs) can operate as a "fine stress-sensing interface", which either triggers prosurvival reconstitution of the damaged organelles or diverges the pathway to cell death [5,12,13]. Moreover, referring to the macroautophagy biogenesis, the ER-MAMmitochondrial structures can originate omegasomes yet essentially contribute to formation, nucleation and elongation of the isolation membranes (phagophores), which further became sources of autophagosomes [5,6,10,16].…”

“…3, 14, 22]. These observations link impairment of autophagy machinery with pathogenesis of severe degenerative diseases and with promotion of aging, chronic viral infections and tumorigenesis, but also tumor cell death [11][12][13][14]17], current book Chpts. 3,14,22].…”

“…3,14,22]. Taking all the above into consideration, autophagy appears to be an efficient prosurvival adaptive and protective cellular mechanism [2,5,6,[12][13][14][15][16].…”