MARCH5 (Membrane Associated Ring-CH-Type Finger 5, also known as MARCHF5 or MITOL) encodes a mitochondrial outer membrane E3 ubiquitin ligase that plays critical roles in mitochondrial quality control, dynamics, and innate immune signaling. MARCH5 ubiquitinates misfolded proteins on the mitochondrial surface, regulates [mitochondrial fission](/mechanisms/mitochondrial-dynamics) by targeting [DRP1](/genes/dnm1l) and [MFN1/2](/genes/mfn2), and controls [MAVS](/genes/mavs)-dependent antiviral signaling. In the context of neurodegeneration, MARCH5 is essential for clearing aggregation-prone proteins that accumulate on mitochondria, and its dysfunction contributes to mitochondrial fragmentation and neuronal death in [Parkinson's disease](/diseases/parkinsons-disease) and [Alzheimer's disease](/diseases/alzheimers-disease).
...
MARCH5 Gene
Overview
MARCH5 (Membrane Associated Ring-CH-Type Finger 5, also known as MARCHF5 or MITOL) encodes a mitochondrial outer membrane E3 ubiquitin ligase that plays critical roles in mitochondrial quality control, dynamics, and innate immune signaling. MARCH5 ubiquitinates misfolded proteins on the mitochondrial surface, regulates [mitochondrial fission](/mechanisms/mitochondrial-dynamics) by targeting [DRP1](/genes/dnm1l) and [MFN1/2](/genes/mfn2), and controls [MAVS](/genes/mavs)-dependent antiviral signaling. In the context of neurodegeneration, MARCH5 is essential for clearing aggregation-prone proteins that accumulate on mitochondria, and its dysfunction contributes to mitochondrial fragmentation and neuronal death in [Parkinson's disease](/diseases/parkinsons-disease) and [Alzheimer's disease](/diseases/alzheimers-disease).
MARCH5 is the primary E3 ubiquitin ligase for outer mitochondrial membrane (OMM) protein quality control:
Ubiquitinates misfolded or damaged OMM proteins, targeting them for proteasomal degradation (mitochondria-associated degradation, MAD)
Substrates include mislocalized tail-anchored proteins, oxidatively damaged membrane proteins, and aggregation-prone substrates
Works with the AAA-ATPase [VCP/p97](/genes/vcp) to extract ubiquitinated OMM proteins for proteasomal degradation
Mitochondrial Dynamics Regulation
MARCH5 regulates the balance between mitochondrial fission and fusion:
Fission: Ubiquitinates [DRP1](/genes/dnm1l) (Dynamin-related protein 1) to modulate its activity and turnover at mitochondrial fission sites
Fusion: Ubiquitinates and regulates turnover of [MFN1](/genes/mfn1) and [MFN2](/genes/mfn2) (Mitofusins) on the OMM
Net effect: MARCH5 loss causes excessive mitochondrial fragmentation due to uncontrolled [DRP1](/proteins/drp1-protein) accumulation and reduced fusogenic capacity
K48-linked ubiquitination of MAVS targets it for proteasomal degradation
This prevents chronic type I interferon production from mitochondrial damage
Relevant to neuroinflammation: MARCH5 deficiency prolongs MAVS-dependent IFN-β signaling, contributing to sterile inflammation
Clearance of Aggregation-Prone Proteins
MARCH5 ubiquitinates disease-associated proteins that accumulate on mitochondria:
Expanded polyQ [huntingtin](/proteins/huntingtin-protein) fragments that associate with the OMM
Mutant [SOD1](/proteins/sod1-protein) aggregates on mitochondria in ALS
[α-Synuclein](/proteins/alpha-synuclein) fragments imported into mitochondria
Disease Associations
Parkinson's Disease
MARCH5 cooperates with [PINK1](/genes/pink1)/[Parkin](/genes/prkn) in mitophagy: MARCH5 performs initial ubiquitination of OMM proteins on damaged mitochondria, while Parkin amplifies the ubiquitin signal
MARCH5 loss impairs mitophagy initiation, leading to accumulation of dysfunctional mitochondria in dopaminergic [neurons](/entities/neurons)
[α-Synuclein](/proteins/alpha-synuclein) overexpression reduces MARCH5 levels in neuronal cells, creating a feed-forward mitochondrial dysfunction loop
MARCH5 ubiquitinates mutant [LRRK2](/genes/lrrk2) (G2019S) on mitochondria, promoting its clearance
MARCH5 expression is reduced in AD hippocampal neurons, correlating with mitochondrial fragmentation
MARCH5 deficiency exacerbates [tau](/proteins/tau)-induced mitochondrial dysfunction through DRP1 dysregulation
MARCH5 overexpression rescues Aβ-induced mitochondrial morphology defects in neuronal cultures
ALS
Mutant [SOD1](/entities/sod1) (G93A, A4V) misfolds and accumulates on the OMM; MARCH5 ubiquitinates misfolded SOD1 for proteasomal clearance
MARCH5 depletion in motor neurons accelerates mutant SOD1 aggregation and cell death
[TDP-43](/genes/tardbp) C-terminal fragments also accumulate on mitochondria and are MARCH5 substrates
Huntington's Disease
Mutant [HTT](/genes/htt) polyQ fragments associate with mitochondria and impair function
MARCH5 ubiquitinates mutant [HTT](/proteins/huntingtin) fragments on the OMM, promoting their degradation
MARCH5 overexpression reduces mitochondria-associated polyQ aggregation in HD models
Expression
Neurons: Moderate expression; essential for neuronal mitochondrial quality control
Brain regions: Enriched in substantia nigra, [hippocampus](/brain-regions/hippocampus), and [cortex](/brain-regions/cortex) — regions with high mitochondrial metabolic demand
Heart and muscle: High expression; critical for cardiac mitochondrial homeostasis
[Yonashiro R et al., A novel mitochondrial ubiquitin ligase plays a critical role in mitochondrial dynamics (2006) (2006)](https://doi.org/10.1038/sj.emboj.7601249)
[Karbowski M et al., The mitochondrial E3 ubiquitin ligase MARCH5 is required for Drp1 dependent mitochondrial division (2007) (2007)](https://doi.org/10.1083/jcb.200611064)
[Yoo YS et al., The mitochondrial ubiquitin ligase MARCH5 resolves MAVS aggregates during antiviral signalling (2015) (2015)](https://doi.org/10.1038/ncomms8910)
[Sugiura A et al., MITOL regulates endoplasmic reticulum-mitochondria contacts via Mitofusin2 (2013) (2013)](https://doi.org/10.1091/mbc.e13-02-0104)
[Nagashima S et al., Roles of mitochondrial ubiquitin ligase MITOL/MARCH5 in mitochondrial dynamics and diseases (2014) (2014)](https://doi.org/10.1093/jb/mvu070)
[Shiiba I et al., MITOL promotes cell survival by degrading Parkin during mitophagy (2021) (2021)](https://doi.org/10.15252/embr.201949097)