RN-seq data of M7 and D5 cybrids with and without CAP treatment

mtDNA haplogroup M7 was less prevalent in a multi-center m.3243A>G disease cohort. Functional studies using cybrids showed that M7 accelerated cell proliferation and shortened G0/G1 cell cycle when compared with cybrid carrying a non-M7 haplogroup (D5). However, mitochondrial function and cell viability were even worse in M7 cybrid than D5 cybrid when treated with mitochondrial oxidative phosphorylation (OXPHOS) inhibitors, indicating that M7 drives negative selection in patients with m.3243A>G during evolution. We further explored the causes of the variation between M7 and D5 cybrids using transcriptomic strategies. The results showed 778 significant differentially expressed genes (DEGs) between D5 and M7 cybrids, of which expression levels of 434 and 344 genes were upregulated and downregulated, respectively, in the M7 cybrid as compared with levels in the D5 cybrid. Of note, there were 1816 significant GEGs between D5 and M7 cybrids upon CAP treatment, of which expression levels of 940 and 876 genes were upregulated and downregulated, respectively. These data suggested more changes in the D5 cybrid than in the M7 cybrid in an OXPHOS-inhibited state. We next performed both GO and KEGG pathway enrichment analyses to determine the contribution of these DEGs to biological performance. Multiple cellular survival and development-related pathways and three signal transduction pathways (PI3K-Akt, FoxO and p38MAPK) were present among all 79 GO biological processes that showed significantly different enrichment between D5 and M7 cybrids, with or without CAP treatment, which indicated that mitochondrial retrograde signaling contributed substantially to the difference in biological performance between D5 and M7 cybrids.