MECHANISMS LINKING mtDNA DAMAGE AND AGING

P11 MITOCHONDRIA AND ARRHYTHMIAS 6DPXHO 'XGOH\1 2 1&DUGLRYDVFXODU ,QVWLWXWH 27KH :DUUHQ $OSHUW 0HGLFDO 6FKRRO RI %URZQ 8QLYHUVLW\ 3URYLGHQFH 5, 8QLWHG 6WDWHV There is a clear relationship between cardiac mechanical dysfunction and arrhythmogenesis, and yet the mechanistic link is unknown. Mechanical dysfunction is accompanied by mitochondrial dysfunction, and we will discuss some of the ways mitochondrial dysfunction can lead to arrhythmogenesis. Mitochondrial 526 downregulate cardiac sodium channels, the main source of current for conduction, and conne[on (C[), the main protein forming low resistance conduction pathway between cells. In this way, mitochondrial 526 slow cardiac electrical conduction and increase arrhythmic risk. Recent work by our group has demonstrated that increased cytosolic 1AD+, because of cardiomyopathy and mitochondria dysfunction, results in decreased ,1a. The link between increased 1AD+ and decreased ,1a appears to be dependent on mitochondrial R26 production. In myopathic animals, either 1AD+ or mitoTEMP2 given systemically could ameliorate arrhythmic risk and reversed abnormal structural changes seen in mitochondria during cardiomyopathy. Conne[in (C[) is a gap Munction protein that provides low-resistance current propagation through ventricular myocytes. +eart failure is associated with renin-angiotensin system (RA6) activation. In a mouse model of cardiac RA6 activation, c-6rc is activated and correlated with sudden arrhythmic death. Prevention of mitochondrial R26 is suf¿cient to decrease spontaneous arrhythmia in these mice. In conclusion, mitochondrial dysfunction could be an important link between mechanical dysfunction and arrhythmic risk, and preventing mitochondrial R26 may prevent mitochondrial inMury and reduce this deleterious signaling. The data above suggest that mitochondrial antio[idants may be antiarrhythmic by raising 1a+ channels and C[ and by preventing mitochondrial ultrastuctural damage.

SDPXHO 'XGOH\

doi: 10.1016/j.freeradbiomed.2013.10.405

P12 MECHANISMS LINKING mtDNA DAMAGE AND AGING $OLFLD 3LFNUHOO1 ;LDR :DQJ2 0LOHQD 3LQWR DQG &DUORV 0RUDHV 11,1'61,+ %HWKHVGD 0' 20' $QGHUVRQ &DQFHU ,QVWLWXWH +RXVWRQ 7; 8QLWHG 6WDWHV 8QLYHUVLW\ RI 0LDPL 8QLWHG 6WDWHV Although mitochondria are intimately linked to the aging process, the contribution of mitochondrial D1A (mtD1A) damage to cellular senescence is largely unknown. :e observed that double-strand breaks to mtD1A by the the e[pression of a mitochondria targeted restriction endonuclease (mito-PVWI) led to activation of cell cycle arrest proteins and decreased cell growth. Importantly, this effect was not seen in cells lacking mtD1A. The induction of cellular stress markers was mediated through a brief increase in the level of reactive o[ygen species (R26). 1otably, premature aging phenotypes developed in a mouse model where we transiently and ubiTuitously e[pressed mito-PstI. Mitotic tissues such as hair follicle and thymic progenitor cells were the most vulnerable. mtD1A damage LQ YLYR also caused accelerated thymus shrinkage by apoptosis and differentiation into adipose tissue, mimicking natural thymic aging. 2ur data indicates that damaged mtD1A preferentially affects proliferating cells and induces senescence by utilizing nuclear cell cycle arrest and D1A damage proteins.

CDUORV 0RUDHV

doi: 10.1016/j.freeradbiomed.2013.10.406

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