A novel multisystem approach uncovers conserved mitochondrial complex I disease phenotypes and suppressors

Mitochondriopathies are a large group of pathological conditions characterized by dysfunction of tissues and organs with high energy needs such as the brain, heart, and skeletal muscles, which highly rely on functional mitochondrial oxidative phosphorylation (OXPHOS). The vast majority of these disorders are ascribed to mutations in nuclear or mitochondrial encoded subunits of complex I (CI), the largest OXPHOS complex. In this study, we develop a multisystemic pipeline for CI-associated disease based on new approach methods (NAMs), which includes non-mammalian models, namely C. elegans and zebrafish, and mammalian cell-based models, such as neuroblastoma cells and induced pluripotent stem cell (iPSC)-derived neural progenitor cells (NPCs) and brain organoids. Systematic characterization of biochemical and neurobehavioral features in these models reveals obvious mitochondrial alterations with no major signs of redox imbalance possibly due compensatory or tissue-specific effects. Conversely, we identify specific pathogenetic features that are consistent across species and are rescued by lutein or vitamin B12, likely acting through non-cell-autonomous mechanisms converging on neurometabolic rewiring. Overall, our findings support the advantage of leveraging different in vitro and in vivo NAM systems with their unique and complementary disease endpoints to uncover critical pathological and quantifiable phenotypes exploitable to identify disease modifiers and suppressors.