Ringer Loss in Uncovers Mitochondrial Complex I Deficits Relevant to Human Parkinson's Disease

Abstract

Tubulin polymerization promoting proteins (TPPPs) are known for their cytoskeletal regulation across species; however, emerging evidence suggests broader cellular functions, including potential roles in mitochondrial biology. Here, we identify the Drosophila homolog of human TPPP, Ringer, as a previously unrecognized regulator of mitochondrial bioenergetics and electron transport chain Complex I (CI) function. Ringer is enriched in the mitochondrial matrix, and its loss results in reduced levels of multiple CI subunits and assembly factors and a significant decrease in CI enzymatic activity. Notably, in addition to TPPP dysfunction, similar deficits are observed in postmortem human Parkinson's disease (PD) brain tissues, underscoring the translational relevance of our Drosophila model. Pharmacological administration of resveratrol, a reactive oxygen species (ROS) scavenger, reduces mitochondrial superoxide levels and improves CI enzymatic activity and ATP production in ringer mutants, demonstrating that targeted antioxidant therapeutics can improve bioenergetic functions in ringer mutants. Together, these findings establish Ringer as a key regulator of mitochondrial bioenergetics and reveal Ringer-induced CI dysfunction as a phenotype relevant to mitochondrial abnormalities observed in PD, and provide a robust and translationally meaningful framework for investigating mitochondrial dysfunction in PD.