Abstract
A causal relationship between Mitofusin (MFN) 2 gene mutations and the hereditary axonal neuropathy Charcot-Marie-Tooth disease type 2A (CMT2A) was described over 15 years ago. During the intervening period much has been learned about MFN2 functioning in mitochondrial fusion, calcium signaling, and quality control, and the consequences of these MFN2 activities on cell metabolism, fitness, and development. Nevertheless, the challenge of defining the central underlying mechanism(s) linking mitochondrial abnormalities to progressive dying-back of peripheral arm and leg nerves in CMT2A is largely unmet. Here, a different perspective of why, in humans, MFN2 dysfunction preferentially impacts peripheral nerves is provided based on recent insights into its role in determining whether individual mitochondria will be fusion-competent and retained within the cell, or are fusion-impaired, sequestered, and eliminated by mitophagy. Evidence for and against a regulatory role of mitofusins in mitochondrial transport is reviewed, nagging questions defined, and implications on mitochondrial fusion, quality control, and neuronal degeneration discussed. Finally, in the context of recently described mitofusin activating peptides and small molecules, an overview is provided of potential therapeutic applications for pharmacological enhancement of mitochondrial fusion and motility in CMT2A and other neurodegenerative conditions.
Highlights
During the intervening period much has been learned about MFN2 functioning in mitochondrial fusion, calcium signaling, and quality control, and the consequences of these MFN2 activities on cell metabolism, fitness, and development
Described by Margaret Fuller and colleagues as the human homologs of Drosophila fuzzy onion (Fzo) (Santel and Fuller, 2001; Santel et al, 2003), MFN1 and MFN2 differ in catalytic GTPase activity essential for mitochondrial fusion (Ishihara et al, 2004), in their ability to localize at endo/sarcoplasmic reticulum and mediate transorganelle calcium signaling (De Brito and Scorrano, 2008; Chan, 2012; Naon et al, 2016; Seidlmayer et al, 2019; Dorn, 2020), and in their proposed roles mediating mitophagic mitochondrial removal (Chen and Dorn, 2013; Gong et al, 2015)
Forced expression or pharmacological activation of either MFN1 or MFN2 can overcome mitochondrial fusion defects resulting from haploinsufficiency in MFN1 or MFN2 null cells (Chen et al, 2003; Rocha et al, 2018), or from dominant suppression by MFN2 mutants (Detmer and Chan, 2007; Rocha et al, 2018; Zhou et al, 2019)
Summary
A causal relationship between Mitofusin (MFN) 2 gene mutations and the hereditary axonal neuropathy Charcot-Marie-Tooth disease type 2A (CMT2A) was described over 15 years ago. Disease severity and progress can be monitored by tests of neuromuscular integrity that reveal areflexia (from lower sensory-motor nerve damage), loss of vibratory and proprioceptive senses (Gemignani et al, 2004; Park et al, 2012), FIGURE 1 | MFN2 mutation class and possible mechanisms mediating CMT2A.
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