In this problem Baris et al. dysfunction due to accumulated mitochondrial DNA mutations (Khrapko et al. 1999 In this problem of Cell Rate of metabolism Baris et al. (2015) statement the intriguing finding that focal deficiencies in mitochondrial oxidative rate of metabolism of about 0.5% of cells in the mouse heart promote cardiac arrhythmias during aging. A similar rate of recurrence of metabolically deficient cardiomyocytes is definitely observed in the aged human being heart (Müller-H?cker 1989 suggesting the same phenomena might contribute to cardiac rhythm instabilities in seniors humans. Unlike the elderly human being heart the heart of aged mice does not typically contain mitochondrially deficient cells. To create a model of mitochondrially deficient cells in human being cardiac ageing the authors produced mice with cardiac-specific manifestation of a dominant-negative mutant of Twinkle the mitochondrial helicase. Twinkle mutants cause an excess of large deletions in mitochondrial DNA which clonally increase to high fractions in a small number of cells causing their oxidative phosphorylation to fail. As a result the tissue becomes a mosaic with occasional deficient cells (~0.5% of cardiomyocytes in Baris et al. 2015 surrounded by normal cells. This obtaining poses a conceptual problem: how could such a low proportion of defective components disrupt the functioning of the entire heart? Hypotheses have been proposed to explain how these rare cells could affect an entire aging organ as caused by mtDNA mutations in diverse tissues including skeletal muscle and colon. In skeletal muscle the mitochondrially deficient zones are short; thus while their overall presence is at ~1% almost every muscle fiber contains such a zone somewhere along its length. Judd Aiken suggested that these deficient zones produce local degeneration and disconnection weakening the entire fiber (Wanagat et al. 2001 In aged colonic mucosa ~15% of cells are mitochondrially deficient constituting entirely deficient colonic crypts that have been proposed to act as penetration points in the old colon (Khrapko and Turnbull 2014 None of the above hypotheses are however pertinent to the heart. What causes arrhythmias TBA-354 in Twinkle mice? The arrhythmias in the aged Twinkle mice manifested as spontaneous premature ventricular contractions (PVCs) and pauses in rhythm that the authors interpret as atrioventricular block. All indices of global electrical function (reflecting sinoatrial-node pacemaker activity electrical conduction and repolarization) were PDGFRB normal and no enhanced mortality was seen. Rhythm disturbances were only observed with the convergence of two factors: aging and swimming stress. No sustained arrhythmias occurred making re-entrant mechanisms unlikely and suggesting that this electrical dysfunction was predominantly the result of focal ectopic TBA-354 activity. Focal ectopic beats are initiated by oscillations of cardiomyocyte transmembrane voltage called afterdepolarizations both early (EADs) and delayed (DADs). Indeed disruption of intracellular Ca2+ regulation known to occur in the aged heart through mitochondrially derived oxidative modification of sarcoplasmic-reticulum Ca2+-release channels (Cooper et al. 2013 causes such oscillations. While aged heart cells are more likely to produce EADs/DADs how do small numbers of isolated mitochondrially deficient cells enhance this phenomenon? The generation and propagation of cellular EADs/DADs are controlled by the electrototonic effect of the surrounding normal cells acting TBA-354 as a current sink (termed source-sink mismatch). The increased frequency of PVCs in aged Twinkle mice indicates a diminished likelihood of source-sink mismatch. The mismatch can be diminished in two ways. One is to have a larger number of adjacent cells producing EADs/DADs (increased source). The second is to decrease the electrical load exerted by the surrounding cells (reduced sink). Arrhythmias were only seen in Twinkle mice under stress (swimming). Intense exercise TBA-354 under a psychologically stressful condition as occurs with the forced-swimming paradigm greatly increases myocardial metabolic demands and engages the sympathetic nervous system. Sympathetic enhancement causes Ca2+ loading and Ca2+ release-channel phosphorylation both of which increase EAD/DAD likelihood (Chen et al. 2014 In addition the associated greatly increased metabolic demand challenges mitochondrially deficient cells causing them to maximize anaerobic metabolism with the production of large quantities of toxic.