# MARCHF5

## Overview
MARCHF5, also known as membrane-associated ring-CH-type finger 5, is a gene that encodes the protein MITOL, a mitochondrial E3 ubiquitin ligase. This protein is integral to mitochondrial dynamics, playing a critical role in the processes of mitochondrial fission and fusion which are essential for maintaining cellular energy balance and integrity. MITOL is characterized as a transmembrane protein localized to the outer mitochondrial membrane and is involved in the ubiquitination of key mitochondrial proteins, thereby regulating their function and stability. The protein's function is crucial for mitochondrial quality control, cellular health, and has implications in various disease processes when dysregulated (Park2010Loss; Yoo2015The).

## Structure
MARCHF5, also known as MITOL, is a mitochondrial ubiquitin ligase that is a transmembrane protein localized to the outer mitochondrial membrane (OMM). The protein consists of 278 amino acids and includes a RING domain crucial for its ubiquitin ligase activity. The structure of MARCHF5 features four transmembrane domains (TMs), with the N-terminal region containing the RING domain. The regions between TM2 and TM3 and the C-terminal region are exposed to the cytosolic side, which are responsible for recognizing various substrates (Nagashima2022Ubiquitin-mediated).

MARCHF5 also contains a GxxxG motif in TM1, which consists of two glycine residues essential for MITOL dimer formation, indicating its quaternary structure involves dimerization. The integrity of the RING domain is vital for the protein's function, as mutations in this domain (H43W and C65S/C68S) result in the loss of ubiquitin ligase activity (Nagashima2022Ubiquitin-mediated).

The context does not provide specific details on the secondary or tertiary structures, prominent folds, post-translational modifications, or splice variant isoforms of MARCHF5. Therefore, these aspects of the molecular structure cannot be described further based on the available information.

## Function
MARCH5, also known as membrane-associated ring-CH-type finger 5, is a mitochondrial E3 ubiquitin ligase that plays a pivotal role in mitochondrial dynamics, specifically in the processes of mitochondrial fission and fusion, which are essential for maintaining cellular energy balance and integrity. Located on the outer mitochondrial membrane, MARCH5 ubiquitinates key proteins involved in these processes, such as dynamin-related protein 1 (Drp1) and mitofusins, thereby regulating their function and stability (Park2010Loss; Yoo2015The).

The activity of MARCH5 is crucial for the proper function and dynamics of mitochondria. It is involved in the degradation of damaged or misfolded proteins within the mitochondria, contributing to mitochondrial quality control and overall cellular health (Yoo2015The). Additionally, MARCH5 plays a role in the immune response by modulating the mitochondrial antiviral signaling protein (MAVS) during viral infections, targeting MAVS aggregates for degradation to regulate antiviral signaling pathways (Yoo2015The).

Loss of MARCH5 function leads to abnormal mitochondrial morphology, such as increased elongation and interconnection of mitochondria, which can trigger cellular stress and senescence. This highlights its essential role in cellular physiology and the potential implications of its dysfunction in disease processes (Park2010Loss; Karbowski2007The).

## Clinical Significance
Mutations in MARCHF5, or alterations in its expression, have been linked to various diseases and conditions primarily due to its role in mitochondrial dynamics. Abnormalities in MARCHF5 function can lead to excessive mitochondrial fission, contributing to mitochondrial dysfunction observed in neurodegenerative diseases such as Parkinson's disease (PD). Under conditions of oxidative stress, typical in neurodegenerative disorders, the dysregulation of MARCHF5 affects the balance of mitochondrial fission and fusion, leading to cellular damage and neuron death (Nie2020Chaperone-mediated).

Furthermore, loss of MARCHF5 function results in abnormal mitochondrial morphology, such as elongation and interconnection, which is associated with cellular senescence. This type of senescence is distinct from aging and can be induced by various stresses, impacting cellular health and contributing to senescence-related diseases (Park2010Loss).

Additionally, impaired mitochondrial fusion caused by mutations in MARCHF5-related genes like Opa1 and Mfn2 is linked to dominant optic atrophy and Charcot-Marie-Tooth disease type 2A (CMT2A), highlighting the critical role of MARCHF5 in maintaining mitochondrial integrity and function (Fang2012Inactivation).

## Interactions
MARCHF5, also known as MITOL, interacts with a variety of proteins to regulate mitochondrial dynamics and cellular processes. It binds to Mfn2 at the outer mitochondrial membrane, modifying it with K63-linked polyubiquitin chains to promote the formation of mitochondria-ER contact sites, crucial for phospholipid transport between the ER and mitochondria (Nagashima2022Ubiquitin-mediated). Additionally, MARCHF5 interacts with Parkin, particularly in the context of Parkin-dependent mitophagy, where it adds a K48-linked polyubiquitin chain to Parkin, promoting its degradation and thus suppressing mitophagy under mild mitochondrial damage (Nagashima2022Ubiquitin-mediated).

In the context of chaperone-mediated autophagy, MARCHF5 binds with key regulators such as HSPA8 and LAMP2A, influencing the protein-protein interaction dynamics based on the expression levels of LAMP2A (Nie2020Chaperone-mediated). MARCHF5 also plays a role in mitochondrial fission by regulating the subcellular trafficking and assembly of Drp1 at mitochondrial division sites (Karbowski2007The). Furthermore, it mediates the ubiquitylation and degradation of Mitofusin 1 (Mfn1) during the G2/M phase of the cell cycle, crucial for mitochondrial morphology regulation (Park2012Mitofusin). These interactions highlight MARCHF5's central role in mitochondrial dynamics and cellular homeostasis.


## References


[1. (Park2010Loss) Yong-Yea Park, Seungmin Lee, Mariusz Karbowski, Albert Neutzner, Richard J. Youle, and Hyeseong Cho. Loss of march5 mitochondrial e3 ubiquitin ligase induces cellular senescence through dynamin-related protein 1 and mitofusin 1. Journal of Cell Science, 123(4):619–626, February 2010. URL: http://dx.doi.org/10.1242/jcs.061481, doi:10.1242/jcs.061481. (187 citations) 10.1242/jcs.061481](https://doi.org/10.1242/jcs.061481)

[2. (Park2012Mitofusin) Yong-Yea Park and Hyeseong Cho. Mitofusin 1 is degraded at g2/m phase through ubiquitylation by march5. Cell Division, 7(1):25, 2012. URL: http://dx.doi.org/10.1186/1747-1028-7-25, doi:10.1186/1747-1028-7-25. (51 citations) 10.1186/1747-1028-7-25](https://doi.org/10.1186/1747-1028-7-25)

[3. (Nie2020Chaperone-mediated) Tiejian Nie, Kai Tao, Lin Zhu, Lu Huang, Sijun Hu, Ruixin Yang, Pingyi Xu, Zixu Mao, and Qian Yang. Chaperone-mediated autophagy controls the turnover of e3 ubiquitin ligase marchf5 and regulates mitochondrial dynamics. Autophagy, 17(10):2923–2938, December 2020. URL: http://dx.doi.org/10.1080/15548627.2020.1848128, doi:10.1080/15548627.2020.1848128. (22 citations) 10.1080/15548627.2020.1848128](https://doi.org/10.1080/15548627.2020.1848128)

[4. (Fang2012Inactivation) Lei Fang, Charles Hemion, David Goldblum, Peter Meyer, Selim Orgül, Stephan Frank, Josef Flammer, and Albert Neutzner. Inactivation of march5 prevents mitochondrial fragmentation and interferes with cell death in a neuronal cell model. PLoS ONE, 7(12):e52637, December 2012. URL: http://dx.doi.org/10.1371/journal.pone.0052637, doi:10.1371/journal.pone.0052637. (24 citations) 10.1371/journal.pone.0052637](https://doi.org/10.1371/journal.pone.0052637)

[5. (Nagashima2022Ubiquitin-mediated) Shun Nagashima, Naoki Ito, Isshin Shiiba, Hiroki Shimura, and Shigeru Yanagi. Ubiquitin-mediated mitochondrial regulation by mitol/marchf5 at a glance. The Journal of Biochemistry, 173(1):1–11, November 2022. URL: http://dx.doi.org/10.1093/jb/mvac092, doi:10.1093/jb/mvac092. (2 citations) 10.1093/jb/mvac092](https://doi.org/10.1093/jb/mvac092)

[6. (Karbowski2007The) Mariusz Karbowski, Albert Neutzner, and Richard J. Youle. The mitochondrial e3 ubiquitin ligase march5 is required for drp1 dependent mitochondrial division. The Journal of Cell Biology, 178(1):71–84, July 2007. URL: http://dx.doi.org/10.1083/jcb.200611064, doi:10.1083/jcb.200611064. (388 citations) 10.1083/jcb.200611064](https://doi.org/10.1083/jcb.200611064)

[7. (Yoo2015The) Young-Suk Yoo, Yong-Yea Park, Jae-Hoon Kim, Hyeseon Cho, Song-Hee Kim, Ho-Soo Lee, Tae-Hwan Kim, You Sun Kim, Youngsoo Lee, Chul-Joong Kim, Jae U Jung, Jong-Soo Lee, and Hyeseong Cho. The mitochondrial ubiquitin ligase march5 resolves mavs aggregates during antiviral signalling. Nature Communications, August 2015. URL: http://dx.doi.org/10.1038/ncomms8910, doi:10.1038/ncomms8910. (124 citations) 10.1038/ncomms8910](https://doi.org/10.1038/ncomms8910)