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 (Δψ_m) and the cellular production of reactive oxygen species were higher in embryonic fibroblasts from Mpv17(-/-) mice. However, despite the elevated Δψ_m, the Mpv17-deficient mitochondria showed signs of accelerated fission. These observations uncover the role of MPV17 as a Δψ_m-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).