Through a series of biochemical studies, epigenomic profiling, and bioinformatic identification, as summarized in Figure 10, our results systematically reveal how mitochondrial TFAM variants or environmental insults can trigger a cascade of events in the mitochondrial dysfunction-metabolism-H3K27ac/active enhancer activity-transcriptome axis that contribute to PD pathogenesis (Figure 10). Here, TFAM is linked to Parkinson disease.