Miro1 and mitochondrial dysfunction in Huntington's disease: Emerging mechanistic links and therapeutic perspectives.

Authors

Sanjeevan Gupta, Snehashis Mandal, Priti Dipa, Neha, Khadga Raj Aran

Published in

Mitochondrion. Pages 102235. Nov 10, 2026. Epub Nov 10, 2026.

Abstract

Huntington's disease (HD) is a chronic, hereditary, and ultimately fatal neurological disorder that is transmitted in an autosomal dominant manner through an abnormal expansion of trinucleotide CAG repeats in the huntingtin gene, which encodes a mutant protein with an expanded polyglutamine tract. HD occurs in approximately 5-10 individuals per 100,000 people worldwide, and is associated with increasing motor dysfunction, cognitive decline and profound neuropsychiatric disorder with a selective vulnerability of the striatal medium spiny neurons. Early and integral to HD pathogenesis is mitochondrial dysfunction, before the onset of clinical symptoms and obvious neurodegeneration. In the context of mitochondrial regulation, the atypical Rho GTPase Miro1 has emerged as a key regulator that integrates mitochondrial motility, calcium sensing, fusion/fission dynamics, and mitophagy. Mutant huntingtin interferes with the assembly of motor-adaptor complexes containing Miro1, mitochondrial transport along axons, the regulation of motility arrest by Ca²⁺-sensing mechanisms, and the degradation of Miro1 by PINK1/Parkin, leading to impaired mitochondrial quality control and propagation of bioenergetic stress. These converging abnormalities are linked to molecular pathology characterised by mitochondrial mislocalization, insufficient mitochondrial turnover and synaptic failure resulting in selective degeneration of HD neurons. A study using zQ175 HD model mice demonstrated that Miro1overexpression partially rescued impaired anterograde mitochondrial transport in striatal neurons. However, this gain-of-function rescue does not establish endogenous Miro1 deficiency or demonstrate that Miro1 dysfunction is a primary driver of HD pathology. This review critically analyses the molecular mechanisms underlying mitochondrial dysfunction in HD, particularly Miro1, its implications for HD neurodegeneration, and its therapeutic potential.

PMID:
43009033
Bibliographic data and abstract were imported from PubMed on 11 Nov 2026.

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