Prolonged inactivity induces mitochondrial dysfunction that activates proteolytic signaling. Increased intramitochondrial Ca2+, disruptions in cardiolipin, STAT3 translocation, and NADPH oxidase crosstalk increase ROS emissions. Dysfunctional mitochondria also release CytC and AIF that activate proteolytic pathways. Mitochondrial fission also results in disrupted energy production and activates FoxO via AMPK. See text for more details. DRP1, dynamin related protein 1; STAT3, signal transducer and activator of transcription 3; AMPK, AMP-activated protein kinase; CytC, cytochrome C; AIF, apoptosis inducing factor; FoxO, forkhead box O; mPTP, mitochondrial permeable transition pore. I, II, III, IV, denote complex I, complex II, complex III, and complex IV of the electron transport chain.