Suppression of mitochondrial heterogeneity via engineered mitochondria for reversion of mitochondrial disease-related phenotypes

Abstract

Abstract Mitochondrial heterogeneity above the biochemical threshold (~50% damaged mitochondria load) induces the symptom manifest of multiple mitochondrial diseases without effective treatment. However, current mitochondria-targeted therapies related to mitochondrial heterogeneity regulation have yielded unsatisfactory clinical incomes due to the risk of damaged mitochondria carryover and the imbalance of mitochondrial homeostasis. Here, we show that engineered mitochondria (Mitochondria-Lipo@mParkin, MLPers) constructed by adhesion of mitophagy-mediated liposomes to the surface of exogenous mitochondria can supply healthy mitochondria via exogenous mitochondria and both remove damaged mitochondria via enhanced mitophagy. MLPers decrease the high level of mitochondrial heterogeneity to less than 30% which is obviously lower than their biochemical threshold, and lead to the reversion of disease-related phenotypes in two mouse models of tricky mitochondrial diseases (Leber’s hereditary optic neuropathy and idiopathic pulmonary fibrosis). The surface adhesion-engineered mitochondria are powerful tools for maintaining homeostasis of mitochondrial pool and offer a translational approach for pan-mitochondrial disease therapies.