Mitofusin 2 Dysfunction and Disease in Mice and Men

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.

Burst mitofusin activation reverses neuromuscular dysfunction in murine CMT2A

“…Neurogenic distal limb muscular atrophy is progressive until the end of the second decade, at which time the disease stabilizes; longevity is normal, but disability is permanent ( Fridman et al, 2015 ; Feely et al, 2011 ). No mouse models of CMT2A recapitulate all of these key clinical features in the absence of confounding developmental phenotypes ( Zhou et al, 2019 ; Detmer et al, 2008 ; Cartoni et al, 2010 ; Bannerman et al, 2016 ; Dorn, 2020 ). Therefore, a prerequisite for proof-of-concept testing of mitofusin activation in vivo was to generate a mouse CMT2A model having greater similarity to the human condition.…”

“…As introduced above, damaging MFN2 mutations are a straightforward cause of CMT2A, but MFN2 multifunctionality complicates delineating the underlying cellular pathology ( Filadi et al, 2018 ; Dorn, 2020 ). For this reason, the specific functional benefits accruing from mitofusin activation in CMT2A cannot unambiguously be defined.…”

“…Neurogenic distal limb muscular atrophy is progressive until the end of the second decade, at which time the disease stabilizes; longevity is normal, but disability is permanent 1,3 . No mouse models of CMT2A recapitulate all of these key clinical features in the absence of confounding developmental phenotypes 15,[26][27][28][29] .…”

Mitochondrial Syndromes Revisited

“…Mitofusin-2 ( MFN2 ) neuropathy must be cited in addition to these “conventional” mitochondrial disorders. The causal relationship between the hereditary axonal neuropathy Charcot–Marie–Tooth disease type 2A (CMT) and MFN2 gene mutations were described at the beginning of the XXI century [ 42 ]. MFN2 dysfunction preferentially impacts peripheral nerves by impairing mitochondrial fusion, transport, and survival.…”

“…These patients have been exhibiting, frequently from childhood, loss of sensory and motor nerve function in the distal limbs, but some patients show proximal limb weakness due to myopathic involvement. Interestingly, while CMT2A is almost always heterozygous, with autosomal dominant inheritance, bi-allelic MFN2 mutations may lead to multiple lipomatosis [ 42 ], which is another rare, but well-known feature of mitochondrial dysfunction (more commonly associated with the m.8344A>G “MERRF” mutation).…”