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1.A.126.  The Mpv17/Pmp22 4 TMS Putative Channel (Mpv17) Family

The 22-kDa peroxisomal membrane protein (PMP22) is a component of peroxisomal membranes. PMP22 seems to be involved in pore forming activity and may contribute to the unspecific permeability of the organelle membrane (Simske 2013). PMP22 is synthesized on free cytosolic ribosomes and then directed to the peroxisome membrane by specific targeting information, although this is not universally accepted (Egawa et al. 2009). Mpv17 is a closely related peroxisomal protein. In mouse, the Mpv17 protein is involved in the development of early-onset glomerulosclerosis. A homolog of Mpv17 in S. cerevisiae has been been found to be an integral membrane protein of the inner mitochondrial membrane where it has been proposed to have a role in ethanol metabolizm and tolerance during heat-shock (Trott and Morano 2004). Defects in MPV17 are associated with mitochondrial DNA depletion syndrome (MDDS) and Navajo neurohepatopathy (NNH) (Karadimas et al. 2006).

Mpv17 is a non-selective cation channel that modulates the membrane potential under normal conditions as well as conditions of oxidative stress (Antonenkov et al. 2015). It has a pore diameter of 1.8 nm, located in the channel's selectivity filter. The channel is weakly cation-selective and shows several subconductance states. Voltage-dependent gating of the channel is regulated by redox conditions and pH and is affected also in mutants mimicking a phosphorylated state. Likewise, the mitochondrial membrane potential (Δψm) and the cellular production of reactive oxygen species were higher in embryonic fibroblasts from Mpv17(-/-) mice. However, despite the elevated Δψm, the Mpv17-deficient mitochondria showed signs of accelerated fission. These observations uncover the role of MPV17 as a Δψm-modulating channel that apparently contributes to mitochondrial homeostasis under different conditions (Antonenkov et al. 2015).

Noise exposure is particularly stressful to hair-cell mitochondria, which must produce enough energy to meet high metabolic demands as well as regulate local intracellular Ca(2+) concentrations. Mitochondrial Inner Membrane Protein 17 (Mpv17) functions as a non-selective cation channel and plays a role in maintaining mitochondrial homeostasis. In zebrafish, hair cells in mpv17(a9/a9) mutants displayed elevated levels of reactive oxygen species (ROS), elevated mitochondrial calcium, hyperpolarized transmembrane potential, and greater vulnerability to neomycin, indicating impaired mitochondrial function (Holmgren and Sheets 2021). Chronically impaired hair-cell mitochondrial activity influences postsynaptic size under homeostatic conditions but does not exacerbate synapse loss following mechanical injury.



References associated with 1.A.126 family:

Antonenkov, V.D., A. Isomursu, D. Mennerich, M.H. Vapola, H. Weiher, T. Kietzmann, and J.K. Hiltunen. (2015). The Human Mitochondrial DNA Depletion Syndrome Gene MPV17 Encodes a Non-selective Channel That Modulates Membrane Potential. J. Biol. Chem. 290: 13840-13861. 25861990
Egawa, K., H. Shibata, S. Yamashita, H. Yurimoto, Y. Sakai, and H. Kato. (2009). Overexpression and purification of rat peroxisomal membrane protein 22, PMP22, in Pichia pastoris. Protein Expr Purif 64: 47-54. 18984054
Holmgren, M. and L. Sheets. (2021). Influence of Mpv17 on Hair-Cell Mitochondrial Homeostasis, Synapse Integrity, and Vulnerability to Damage in the Zebrafish Lateral Line. Front Cell Neurosci 15: 693375. 34413725
Karadimas, C.L., T.H. Vu, S.A. Holve, P. Chronopoulou, C. Quinzii, S.D. Johnsen, J. Kurth, E. Eggers, L. Palenzuela, K. Tanji, E. Bonilla, D.C. De Vivo, S. DiMauro, and M. Hirano. (2006). Navajo neurohepatopathy is caused by a mutation in the MPV17 gene. Am J Hum Genet 79: 544-548. 16909392
Magyar, J.P., C. Ebensperger, N. Schaeren-Wiemers, and U. Suter. (1997). Myelin and lymphocyte protein (MAL/MVP17/VIP17) and plasmolipin are members of an extended gene family. Gene 189: 269-275. 9168137
Martorano, L., M. Peron, C. Laquatra, E. Lidron, N. Facchinello, G. Meneghetti, N. Tiso, A. Rasola, D. Ghezzi, and F. Argenton. (2019). The zebrafish orthologue of the human hepatocerebral disease gene plays pleiotropic roles in mitochondria. Dis Model Mech 12:. 30833296
Simske, J.S. (2013). Claudins reign: The claudin/EMP/PMP22/γ channel protein family in C. elegans. Tissue Barriers 1: e25502. 24665403
Trott, A. and K.A. Morano. (2004). SYM1 is the stress-induced Saccharomyces cerevisiae ortholog of the mammalian kidney disease gene Mpv17 and is required for ethanol metabolism and tolerance during heat shock. Eukaryot. Cell. 3: 620-631. 15189984