To identify significantly altered functional groups under the dysfunctional r 0 state, we organized mt proteins into functional modules (right panel in Figure 1A ). We identified modules by examining whether a group of proteins was physically connected or functionally linked. We used hierarchical average-linkage clustering with the STRING confidence scores as a similarity measure (Materials and Methods for details). Then, we assigned the biological function to the module by examining the representative functional annotations from proteins in each module. Finally, we identified 13 functional modules that were enriched either within up-regulated or down-regulated protein groups (p-value ,0.01; Table S3 ). As shown in Figure 3A , five functional groups were up-regulated (shown in green boxes), whereas eight functional groups were down-regulated (shown in red boxes) under the dysfunctional r 0 state. The five up-regulated groups contain 59 out of 89 (66.29%) up-regulated proteins. They are linked to the function of cytosolic ribosome, ribonucleoprotein complex, protein folding on mt surface, DNA repair, and proteolysis, which are associated with the regulation of mt protein expression in response to mtDNA damage ( Figure 3B ). Conversely, the eight down-regulated groups include 138 out of 175 (78.86%) down-regulated proteins. They were associated with basal mt functions, such as mitochondrial energy production, metabolism, and protein folding in mitochondria ( Figure 3C ). Our result suggests that the expression control of mt proteins that are involved in different functional modules is regulated separately under dysfunctional mt states.