Iron dysregulation drives respiratory and locomotor deficits in mitochondrial MPV17 deficiency

Genetic perturbation in the inner mitochondrial membrane protein MPV17 causes hepatocerebral mitochondrial DNA (mtDNA) depletion syndrome with nonfunctional mitochondrial respiratory chain biogenesis in humans. However, existing disease models fail to establish MPV17’s molecular role and to recapitulate the neurological deficits. To overcome this limitation and elucidate the underlying disease mechanism, we utilized yeast Saccharomyces cerevisiae and Caenorhabditis elegans worm models alongside compound screening that restores respiratory defects of MPV17 deletion. Our study uncovered that the yeast ortholog, Stress-induced MPV17 ( SYM1 ), knockout S. cerevisiae cells have ~50% reduced total iron and significantly downregulated Fe-S-containing respiratory enzyme activities under the higher 37 °C temperature stress. Moreover, supplementation with ferrous ammonium sulfate (FAS), which increases cellular iron levels, restores the respiratory growth of SYM1- deleted S. cerevisiae cells. Similarly, we found that loss of mpv-17 in C. elegans reduced iron levels, diminished mitochondrial respiratory activity, and caused severe developmental and locomotor defects, including impaired egg laying, omega turns, body bends, and thrashing behaviors. Remarkably, FAS supplementation significantly rescued these locomotor defects in vivo , demonstrating that restricted iron availability is the primary driver of cellular dysfunction in mpv-17 -deleted C. elegans . Using purified human MPV17 protein, we further show that MPV17 binds exclusively to Fe 2+ ions. Furthermore, silencing of MPV17 in human liver HepG2 cells showed changes in mitochondrial morphology and reduction in ATP synthesis. Because proper neuronal development relies on robust mitochondrial respiration and iron-dependent metabolism, these findings together establish a direct causal link between mitochondrial MPV17 and iron regulation and neurological development.