Project Grant R01NS134932

HARNESSING MITOCHONDRIA TRANSFER PATHWAYS TO AMELIORATE LEIGH SYNDROME-LIKE DISEASE - PROJECT SUMMARY LEIGH SYNDROME (LS) IS AN INHERITED MITOCHONDRIAL DISEASE THAT PRESENTS WITH PROMINENT NEUROLOGIC SYMPTOMS AND DEATH IN CHILDHOOD. THERE ARE CURRENTLY NO EFFECTIVE THERAPIES FOR THIS DEVASTATING DISEASE, HIGHLIGHTING AN URGENT NEED TO IDENTIFY NOVEL BIOLOGICAL PATHWAYS THAT CAN BE TARGETED THERAPEUTICALLY TO TREAT LS AND OTHER INHERITED MITOCHONDRIAL DISEASES. OVER THE PAST 15 YEARS, AN EMERGING BODY OF RESEARCH, INCLUDING RECENT STUDIES BY US (BRESTOFF ET AL., CELL METABOLISM, 2021 ), INDICATES THAT MANY CELL TYPES EXPORT THEIR MITOCHONDRIA FOR DELIVERY TO NEIGHBORING CELLS, INCLUDING NEURONS, IN VIVO IN A PROCESS CALLED INTERCE/LULAR MITOCHONDRIA TRANSFER. OUR LABORATORY ALSO RECENTLY REPORTED THAT ADMINISTERING PURIFIED MITOCHONDRIA TO NDUFS4-1- MICE WITH LS COMPLETELY RESTORES THE CELL-INTRINSIC DEFECTS IN MITOCHONDRIAL METABOLISM OF MACROPHAGES (BORCHERDING ET AL., CELL METABOLISM, 2022). HOWEVER, IT IS UNKNOWN WHETHER INTERCELLULAR MITOCHONDRIA TRANSFER CAN BE HARNESSED THERAPEUTICALLY TO TREAT LS. IN NEW PRELIMINARY STUDIES, WE FOUND THAT WEEKLY SYSTEMIC ADMINISTRATION OF PURIFIED WILDTYPE (WT) MITOCHONDRIA TO NDUFS4-1- MICE INCREASED THEIR LIFESPAN AND MARKEDLY REDUCED THEIR NEUROLOGIC MORBIDITY AND NEURODEGENERATION. THESE DATA PROVOKE OUR HYPOTHESIS THAT ADMINISTERING EXOGENOUS MITOCHONDRIA CAN RESCUE THE METABOLISM OF RECIPIENT CELLS AND MAY BE A PREVIOUSLY UNKNOWN THERAPEUTIC STRATEGY FOR LS. EXOGENOUS MITOCHONDRIA APPEAR TO BE CAPTURED FIRST BY MACROPHAGES, WHICH ARE MOBILE CELLS THAT CAN LATER EXPORT CAPTURED MITOCHONDRIA TO NEIGHBORING CELLS. BASED ON THIS FINDING, WE TRANSPLANTED WT BONE MARROW INTO NDUFS4-1 - HOSTS AND FOUND THAT THIS INTERVENTION LED TO DELIVERY OF HEALTHY DONOR CELL-DERIVED MITOCHONDRIA TO HOST CELLS, AMELIORATED LS SEVERITY, AND EXTENDED THEIR LIFESPAN. THESE DATA SUGGEST THAT ENGRAFTED IMMUNE CELLS FROM BONE MARROW TRANSPLANTATION CAN PROVIDE A SYSTEMICALLY DISTRIBUTED, SELF-RENEWING SUPPLY OF HEALTHY MITOCHONDRIA TO DISEASED CELLS IN VIVO. COLLECTIVELY. THESE DATA PROVOKE OUR CENTRAL HYPOTHESIS THAT PROVIDING SOURCES OF HEALTHY MITOCHONDRIA POSTNATALLY MAY AMELIORATE LS BY RESCUING CELL-INTRINSIC METABOLIC DEFECTS. WE WILL ADDRESS THIS HYPOTHESIS IN TWO AIMS. IN AIM 1, WE WILL DETERMINE HOW ADMINISTERING EXOGENOUS MITOCHONDRIA IMPROVES THE MORBIDITY AND MORTALITY OF LS. IN AIM 2, WE WILL INVESTIGATE HOW BONE MARROW TRANSPLANTATION IMPROVES LS BY PROVIDING A DURABLE, SYSTEMICALLY DISTRIBUTED SOURCE OF HEALTHY MITOCHONDRIA. THIS HIGHLY INNOVATIVE PROJECT WILL LEVERAGE OUR EXPERTISE IN INTERCELLULAR MITOCHONDRIA TRANSFER AND NEW CUTTING-EDGE TECHNOLOGIES TO ESTABLISH THE EFFICACY OF AND IDENTIFY THE MECHANISMS OF THESE TWO NOVEL THERAPEUTIC STRATEGIES TO TREAT FATAL INHERITED MITOCHONDRIAL DISEASES SUCH AS LS.