Mitochondrial dysfunction is associated with a pro-apoptotic cellular environment in senescent cardiac muscle.
Cardiac muscle undergoes significant remodeling with aging. This may be partly due to the progressive impairment of mitochondrial biogenesis and function. Our purpose was to examine how aging affects the subcellular localization of apoptogenic factors involved in mitochondrially mediated cell death in cardiac muscle. Employing 6- and 36-month-old Fischer 344xBN animals, we assessed markers of organelle content and function, as well as the mitochondrial and cytosolic compartmentalization of proteins implicated in apoptosis. Aging was associated with decrements in cardiac mitochondrial content and respiratory function. These changes were accompanied by a greater cytosolic accumulation of cytochrome c and AIF, as well as a higher mitochondrial Bax and a faster rate of permeability transition pore opening. Mitochondria from aged hearts demonstrated a greater enrichment of p66Shc and p46Shc providing further evidence of enhanced apoptogenic signaling. Opa1 was greater in the senescent myocardium, while Drp1 was higher in the mitochondrial fraction of aged, compared to the young animals. Furthermore, the level of fragmented DNA was greater in the hearts of senescent animals. Thus, the specific compartmentalization of apoptogenic proteins implies that mitochondrially mediated cell death signaling is highly active in the aged myocardium, which may contribute to progressive cardiac pathophysiology.
Ljubicic
Vladimir
V
School of Kinesiology and Health Science, York University, Toronto, Ontario M3J 1P3, Canada.
Menzies
Keir J
KJ
Hood
David A
DA
D000375:Aging / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D003574:Cytochrome c Group / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism*; D010539:Permeability; D051381:Rats; D011916:Rats, Inbred F344; D015398:Signal Transduction / Q000502:physiology; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D003574:Cytochrome c Group; D051028:bcl-2-Associated X Protein; C076615:cytochrome c''; D045304:Cytochromes c