Investigation of mitochondrial biogenesis defects in single substantia nigra neurons using post-mortem human tissues

Mitochondrial respiratory chain deficiency and mitochondrial DNA deletions are reported in substantia nigra neurons from healthy aged and Parkinson's disease cases, with extensive neuronal loss only seen in the latter. This study aimed to understand the pathological relevance of mitochondrial defects for neuronal survival. Using post-mortem human midbrain, substantia nigra neurons exposed to different types of mitochondrial defects (including mitochondrial DNA point mutations, single and multiple deletions) were compared to neurons from healthy aged and Parkinson's disease cases (either sex) at a single neuronal level. We identified mitochondrial deficiencies in all cases, though these deficiencies were more severe in the mitochondrial disease patients with multiple deletions. A significant reduction in TFAM expression was detected in Parkinson's disease compared to cases with other mitochondrial defects. Higher mitochondrial DNA copy number was detected in healthy aged neurons, despite a deletion level equivalent to Parkinson's disease. Our data support that in individuals with pathogenic mitochondrial defects, neurons respond to mitochondrial defect to survive and such an adaptation may involve TFAM.