Regulation of Mitochondrial Dynamics by Proteolytic Processing and Protein Turnover

Abstract

The mitochondrial network is a dynamic organization within eukaryotic cells that participates in a variety of essential cellular processes, such as ATP synthesis, central metabolism, apoptosis and inflammation. The mitochondrial network is balanced between rates of fusion and fission that respond to pathophysiologic signals to coordinate appropriate mitochondrial processes. Mitochondrial fusion and fission are regulated by proteins that either reside or translocate to the inner or outer mitochondrial membranes or are soluble in the inter-membrane space. Mitochondrial fission and fusion are performed by GTPases on the outer and inner mitochondrial membranes with the assistance of other mitochondrial proteins. Due to the essential nature of mitochondrial function for cellular homeostasis regulation of mitochondrial dynamics is under strict control. Some of the mechanisms used to regulate the function of these proteins are post-translational proteolysis and/or turnover and this review will discuss these mechanisms required for correct mitochondrial network organization. IntroductionMitochondria are the power houses of every nucleated cell, generating chemical energy in the form of adenosine triphosphate (ATP) by the oxidative phosphorylation (OXPHOS) system. Mitochondria are also important for the normal functioning of the cells as they regulate several crucial activities like differentiation, cell cycle, intracellular signaling and cell death [1]. Mitochondria are unique because of their autonomous DNA (mtDNA), which encodes for proteins required for ATP synthesis. Therefore maintenance of mtDNA is important for normal mitochondrial function and for the diversity of mitochondrial genome [2]. Mitochondria form elongated tubules that continually divide and fuse to form a complex, interconnected and highly dynamic network inside of cells. These dynamics processes not only regulate mitochondrial function but also mitochondrial shape, content exchange and mitochondrial communication with the cytoskeleton [3]. Due to the involvement of mitochondria in a large spectrum of cellular functions, these organelles play a key role in mediating cellular homeostasis. As a result a healthy population of mitochondria is critical for cell survival.

Characterization of MCU-Binding Proteins MCUR1 and CCDC90B — Representatives of a Protein Family Conserved in Prokaryotes and Eukaryotic Organelles

“…Although both fulllength and processed MCUR1 bind MCU, it remains unclear whether they are also functionally equivalent. It is entirely possible that MCUR1 activity and stability are proteolytically regulated, similar to what is reported for EMRE during MCU complex formation and other mitochondrial proteins, such as dynamin-like GTPase OPA1 and Parkinson disease-related Ser/Thr kinase PINK1 (Ali and McStay, 2018).…”

ISG15, a Small Molecule with Huge Implications: Regulation of Mitochondrial Homeostasis

“…Its covalent conjugation to target proteins has proteolytic and non-proteolytic or regulatory outcomes, which fine-tune protein function and recycling [ 113 ]. Indeed, ubiquitylation is essential for the regulation of many mitochondrial processes, such as mitophagy [ 95 , 114 , 115 , 116 ], mitochondrial dynamics [ 117 , 118 ], and mitochondria-related immune signaling [ 86 , 119 , 120 ], establishing the importance of this modifier in the homeostasis of these organelles.…”

Mitochondrial Dynamics of Proximal Tubular Epithelial Cells in Nephropathic Cystinosis

“…Mitochondrial dynamics is balanced between rates of fusion and fission that respond to pathophysiologic signals. This finely regulated equilibrium is closely related to the quality control system, which is mainly ascribed to the ubiquitin protease system (UPS) and to the intra-mitochondrial proteolytic systems [33]. In our experimental model, no significant differences were observed on protein levels of phosphorylated Drp1 at Ser-637.…”