Glial mitochondrial function and dysfunction in health and neurodegeneration

Mitochondria play essential metabolic roles in neural cells. Mitochondrial dysfunction has profound effects on the brain. In primary mitochondrial diseases, mutations that impair specific oxidative phosphorylation (OXPHOS) proteins or OXPHOS assembly factors lead to isolated biochemical defects and a heterogeneous group of clinical phenotypes, including mitochondria] encephalopathies. A broader defect of OXPHOS function, due to mutations in proteins involved in mitochondria] DNA maintenance, mitochondrial biogenesis, or mitochondria] tRNAs can also underlie severe mitochondrial encephalopathies. While primary mitochondria] dysfunction causes rare genetic forms of neurological disorders, secondary mitochondrial dysfunction is involved in the pathophysiology of some of the most common neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Many studies have investigated mitochondrial function and dysfunction in bulk central nervous system (CNS) tissue. However, the interpretation of these studies has been often complicated by the extreme cellular heterogeneity of the CNS, which includes many different types of neurons and glial cells. Because neurons are especially dependent on OXPHOS for ATP generation, mitochondrial dysfunction is thought to be directly involved in cell autonomous neuronal demise. Despite being metabolically more flexible than neurons, glial mitochondria also play an essential role in the function of the CNS, and have adapted specific metabolic and mitochondrial features to support their diversity of functions. This review analyzes our current understanding and the gaps in knowledge of mitochondrial properties of glia and how they affect neuronal functions, in health and disease.