We found that functional modules controlling mt protein translation, folding, proteolysis, and mtDNA repair were upregulated in the dysfunctional r 0 state (Figure 3 ). To properly respond to changes in cellular states, these processes may require retrograde regulation [35] . Retrograde signaling regulates many cellular activities under pathophysiological conditions by changing the protein inventories of subcellular organelles. It may be possible that up-regulated mt proteins shuttle between the mitochondria and other organelles for intracellular communication [40] . Indeed, we found that the proteins of up-regulated functional modules tended to have multiple annotations of subcellular localization and to be involved in processes occurring inside and outside of mitochondria (Table S1 ). For example, AP-endonuclease 1 (APEX1) of the DNA repair module is known to shuttle from mitochondria to the nucleus in response to oxidative stress [41] . Heterogeneous nuclear ribonucleoprotein K (HNRPK), a member of the ribonucleoprotein complex associated with mtDNA transcription, has been detected in the nucleus, cytoplasm, and mitochondria [42] . These observations suggest that up-regulated functional modules act as cross-talk components connecting mitochondria with other organelles to sense and propagate the We observed that up-regulated and down-regulated functional modules contain a small fraction of proteins with opposite protein expression patterns (Figure 3 ). On average, levels of 5.5% of the proteins in down-regulated functional modules were increased, while levels of 4.7% of the proteins in up-regulated functional modules were decreased under the dysfunctional r 0 state. Proteins with opposite expression patterns in the functional module could act as negative regulators of the module [43] . For example, in the TCA cycle module, acetolactate synthase (AHAS) was upregulated, while other proteins were down-regulated. It has been reported that upregulation of AHAS decreases the activity of the TCA cycle by reducing pyruvate flow into the cycle [44] . In addition, ATP6V1B2 and ATP6V1G1 in the ATP synthesis module were up-regulated, while other proteins were downregulated. Upregulation of these proteins is known to participate in ATP hydrolysis, leading to the downregulation of ATP synthesis [45] . Moreover, two heat shock proteins, HSP90AA1 and HSP90AB1, involved in protein folding on the mt surface were down-regulated, while other proteins were up-regulated. The heat shock proteins regulate chaperone activity in response to ATP concentrations in the cell [46] . Under the dysfunctional r 0 state, ATP reduction could induce the disruption of HSP90 chaperone activity. Thus, we suspect that oppositely expressed proteins may compensate for the function of other proteins in the same modules.