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. 

ATI-2307 represents a novel class of antifungal agents, whose mechanism is limited to yeasts via two mechanisms (Giamberardino et al. 2023). First, ATI-2307 is preferentially taken up into fungal cells relative to mammalian cells via a high affinity carrier mechanism regulated by Agp2, which is only present in fungal cells. Second, once internalized, ATI-2307 selectively disrupts the yeast mitochondrial membrane potential and respiratory chain resulting in rapid yeast cell death. While ATI-2307 collapsed the membrane potential of mitochondria isolated from Saccharomyces cerevisiae at 20 µM, it had no effect on the membrane potential of rat liver mitochondria (Giamberardino et al. 2023).

   
     

 


 

References:

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.

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.

Giamberardino, C.D., J.L. Tenor, D.L. Toffaletti, J.R. Palmucci, W. Schell, J.K. Boua, C. Marius, K.E. Stott, S.L. Steele, W. Hope, D. Cilla, and J.R. Perfect. (2023). Pharmacodynamics of ATI-2307 in a rabbit model of cryptococcal meningoencephalitis. Antimicrob. Agents Chemother. e0081823. [Epub: Ahead of Print]

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.

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.

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.

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:.

Simske, J.S. (2013). Claudins reign: The claudin/EMP/PMP22/γ channel protein family in C. elegans. Tissue Barriers 1: e25502.

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.

Examples:

TC#NameOrganismal TypeExample
1.A.126.1.1

Mitochondrial membrane Mpv17 (also called MAL and VIP17) protein of 176 aas and 4 TMSsv (Magyar et al. 1997).

Animals

Mpv17 of Homo sapiens

 
1.A.126.1.10

Mitogen-activated protein kinase 1 with an N-terminal Mpv17 domain preceding the C-terminal kinase domain of 911 aas and 5 - 7 TMSs in the N-terminal domain.

Mpv17- protein kiinase protein of Symbiodinium microadriaticum

 
1.A.126.1.11

Uncharacterized protein of 287 aas with a 150 aas N-terminal hydrophilic domain and a C-terminal Mpv17 domain with 4 TMSs.

UP of Medioppia subpectinata

 
1.A.126.1.12

Uncharacterized protein of 268 aas and 5 TMSs, one N-terminal, followed by a 120 residues hydrophilic domain followed by the 4 TMS Mpv17 domain.

UP of Chrysochromulina tobinii

 
1.A.126.1.2

Mpv17 domain protein of 197 aas and 4 TMSs, Sym1.

Fungi

Sym1 of Saccharomyces cerevisiae

 
1.A.126.1.3

Peroxisomal membrane protein, Pmp22 or Pxmp2 of 195 aas and 4 TMSs.  Seems to be involved in pore-formation and may contribute to the non-specific permeability of the peroxisomal membrane although this has been questioned (Egawa et al. 2009).

Animals

Pxmp2 of Homo sapiens

 
1.A.126.1.4

Mpv17 of 177 aas and 4 TMSs. It is involved in mitochondrial homeostasis, and control of oxidative phosphorylation and mitochondrial DNA (mtDNA) maintenance (Martorano et al. 2019). It is a non-selective cation channel that modulates the membrane potential under normal conditions as well as conditions of oxidative stress (See TC# 1.A.126.1.5).

Mpv17 of Danio rerio (Zebrafish) (Brachydanio rerio)

 
1.A.126.1.5

Mpv17 of 176 aas and 4 TMSs. It 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 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.

Mpv17 of Mus musculus

 
1.A.126.1.6

PXMP2/4 family protein, 4-like of 264 aas and 4 - 6 TMSs.

PXMP2/4 protein of Gossypium raimondii

 
1.A.126.1.7

Glomerulosclerosis Mpv17 of 249 aas and 4 TMSs.

Mpv17 of Fusarium mexicanum

 
1.A.126.1.8

Uncharacterized protein of 314 aas and 4 TMSs.

UP of Thalassiosira pseudonana

 
1.A.126.1.9

Uncharacterized protein of 293 aas and 5 - 7 TMSs, with four distinct hydrophobic peaks in the C-terminal half of the protein plus 1 - 3 TMSs in the N-terminal half.

UP of Chlorella variabilis