Wednesday, February 5, 2025
2/5/2025
Neurons depend on mitochondria to supply energy for processes such as synaptic transmission, channel activity, and axonal transport. To meet the constantly changing energy demands of neurons, mitochondria undergo frequent fission and fusion. Fission and fusion enhance respiration, ATP synthesis, Ca2+ homeostasis, clearance of damaged organelles by mitophagy, neuronal function, and cell survival. However, excessive fission and lack of fusion can cause mitochondrial fragmentation and is implicated in neurodegeneration. Mitochondrial fission and fusion are regulated by large GTPases of the dynamin family. Optic Atrophy 1 (OPA1) is required for mitochondrial inner membrane fusion and maintenance of cristae structure, mtDNA, respiration, ATP synthesis, Ca2+ homeostasis, and neuronal cell survival. Significantly, autosomal dominant mutations in OPA1 cause a spectrum of neurodegenerative disorders, including dominant optic atrophy (DOA), characterized by degeneration of retinal ganglion cells (RGCs) and optic nerve axons. The majority of OPA1 missense mutations are located in the conserved GTPase (G) domain and interfere with normal OPA1 function by dominant-negative mechanisms. Thus, inactivation of the G-domain is associated with disease pathogenesis. While OPA1 mutations cause early-onset familial forms of neurodegenerative disease, it is unknown whether OPA1 can also be inactivated in late-onset sporadic diseases. Remarkably, recent high-throughput proteomic screens identified a major lysine acetylation site located in the G-domain and a hotspot of pathogenic OPA1 mutations, predicting a critical functional role. The function of this posttranslational modification (PTM) is unknown. In addition, research tools to investigate the significance of OPA1 lysine acetylation are currently missing. Here, we will investigate whether lysine acetylation in the G-domain is a new PTM regulating OPA1 function. We will address the following questions: (1) Does acetylation inhibit OPA1 GTP hydrolysis? (2) Does acetylated OPA1 inhibit mitochondrial fusion and function? (3) Does OPA1 acetylation play a causal role in neuronal injury and cell death? Lysine acetylation might emerge as a novel mechanism of OPA1 inactivation during aging and contribute to mitochondrial fragmentation and dysfunction in sporadic neurodegenerative disorders. Modulating OPA1 acetylation might be a new neuroprotective strategy.
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