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. Differential adaption of SN neurons to mitochondrial defect and its association with SN neurodegeneration. Display omitted •A significant decrease in TFAM expression and total mtDNA copy number in PD neurons containing multiple mtDNA deletions.•A decrease in TFAM expression was not observed in SN neurons from POLG patients, also harbouring multiple mtDNA deletions.•mtDNA copy number could be more determinant for the OXPHOS phenotype of mitochondria in the SN neurons than deletion load.