Redox Modifications of Proteins of the Mitochondrial Fusion and Fission Machinery

Abstract

Mitochondrial fusion and fission tailors the mitochondrial shape to changes in cellular homeostasis. Players of this process are the mitofusins, which regulate fusion of the outer mitochondrial membrane, and the fission protein DRP1. Upon specific stimuli, DRP1 translocates to the mitochondria, where it interacts with its receptors FIS1, MFF, and MID49/51. Another fission factor of clinical relevance is GDAP1. Here, we identify and discuss cysteine residues of these proteins that are conserved in phylogenetically distant organisms and which represent potential sites of posttranslational redox modifications. We reveal that worms and flies possess only a single mitofusin, which in vertebrates diverged into MFN1 and MFN2. All mitofusins contain four conserved cysteines in addition to cysteine 684 in MFN2, a site involved in mitochondrial hyperfusion. DRP1 and FIS1 are also evolutionarily conserved but only DRP1 contains four conserved cysteine residues besides cysteine 644, a specific site of nitrosylation. MFF and MID49/51 are only present in the vertebrate lineage. GDAP1 is missing in the nematode genome and contains no conserved cysteine residues. Our analysis suggests that the function of the evolutionarily oldest proteins of the mitochondrial fusion and fission machinery, the mitofusins and DRP1 but not FIS1, might be altered by redox modifications.

Neuronal AMPK coordinates mitochondrial energy sensing and hypoxia resistance inC. elegans

“…One example of note may be through autophagy, which is controlled by AMPK signaling in some circumstances 73 . Mitochondrial uncoupling can induce autophagy and changes in mitochondrial morphology 74–76 . The mechanisms of mitochondrial fission and fusion downstream of dissipated PMF are under investigation in many contexts, and deeper understanding in these areas could further solidify the link between energy metabolism and AMPK‐mediated cell signaling.…”

Insulin Resistance at the Crossroad of Alzheimer Disease Pathology: A Review

“…Most of Drp1 is localized in the cytoplasm, but a small part is found in the OMM especially upon activation where it oligomerizes and encircles the mitochondrion, thereby inducing fragmentation (250,251). The pro-fission activity of Drp1 is regulated by phosphorylation, ubiquitination, SUMOylation and S-nitrosylation processes (252). Drp1 is also involved in apoptosis induction via BAX and cytochrome c release (238).…”

Abnormalities of synaptic mitochondria in autism spectrum disorder and related neurodevelopmental disorders

“…Meanwhile, phosphorylation at Ser637 by protein kinase A (PKA) and Ca 2+ /calmodulin-dependent protein kinase Iα (CaMKIα) inhibits mitochondrial fission [ 57 , 58 ]. Modifications like nitrosylation promote Drp1 phosphorylation at Ser616, and consequently, mitochondrial fission in primary hippocampal neurons [ 59 , 60 ]. Mitochondrial fusion and fission need to be balanced for neuronal health [ 61 ].…”