TY - JOUR
T1 - Vascular mitochondrial respiratory function
T2 - The impact of advancing age
AU - Park, Soung Hun
AU - Kwon, Oh Sung
AU - Park, Song Young
AU - Weavil, Joshua C.
AU - Andtbacka, Robert H.I.
AU - Hyngstrom, John R.
AU - Reese, Van
AU - Richardson, Russell S.
N1 - Funding Information:
This work was funded, in part, by National Heart, Lung, and Blood Institute Grant PO1-HL-1091830 and Veterans Administration Rehabilitation Research and Development Service Grants E6910-R, E1697-R, E1433-P, E9275-L, and E1572-P.
PY - 2018/12
Y1 - 2018/12
N2 - Little is known about vas-cular mitochondrial respiratory function and the impact of age. Therefore, skeletal muscle feed arteries were harvested from young (33 = 7 yr, n ± 10), middle-aged (54 = 5 yr, n ± 10), and old (70 = 7 yr, n ± 10) subjects, and mitochondrial respiration as well as citrate synthase (CS) activity were assessed. Complex I (CI) and complex I < II (CI<II) state 3 respiration were greater in young (CI: 10.4 = 0.8 pmol·s‒1·mg‒1 and CI<II: 12.4 = 0.8 pmol·s‒1·mg‒1, P < 0.05) than middle-aged (CI: 7 = 0.6 pmol·s‒1·mg‒1 and CI<II: 8.3 = 0.5 pmol·s‒1·mg‒1) and old (CI: 7.2 = 0.4 pmol·s‒1·mg‒1 and CI<II: 7.6 = 0.5 pmol·s‒1·mg‒1) subjects and, as in the case of complex II (CII) state 3 respiration, were inversely correlated with age [r ±>0.56 (CI), r ±>0.7 (CI<II), and r ± 0.4 (CII), P < 0.05]. In contrast, state 4 respiration and mitochondria-specific superoxide levels were not different across groups. The respiratory control ratio was greater in young (2.2 = 0.2, P < 0.05) than middle-aged and old (1.4 = 0.1 and 1.1 = 0.1, respectively) subjects and inversely correlated with age (r ±>0.71, P < 0.05). As CS activity was inversely correlated with age (r ±>0.54, P < 0.05), when normalized for mitochondrial content, the age-related differences and relationships with state 3 respiration were ablated. In contrast, mitochondrion-specific state 4 respiration was now lower in young (15 = 1.4 pmol·s‒1·mg‒1·U CS‒1, P < 0.05) than middle-aged and old (23.4 = 3.6 and 27.9 = 3.4 pmol·s‒1·mg‒1·U CS‒1, respectively) subjects and correlated with age (r ± 0.46, P < 0.05). Similarly, superoxide/CS levels were lower in young (0.07 = 0.01) than old (0.19 = 0.41) subjects and correlated with age (r ± 0.44, P < 0.05). Therefore, with aging, vascular mitochondrial respiratory function declines, predominantly as a consequence of falling mitochondrial content. However, per mitochondrion, aging likely results in greater mitochondrion-derived oxidative stress, which may contribute to age-related vascular dysfunction. NEW & NOTEWORTHY This study determined, for the first time, that vascular mitochondrial oxidative respiratory capacity, oxidative coupling efficiency, and mitochondrial content fell progressively with advancing age. In terms of single mitochondrion-specific respiration, the age-related differences were completely ablated and the likelihood of free radical production increased progressively with advancing age. This study reveals that vascular mitochondrial respiratory capacity declines with advancing age, as a consequence of falling mitochondrial content, as does oxidative coupling efficiency.
AB - Little is known about vas-cular mitochondrial respiratory function and the impact of age. Therefore, skeletal muscle feed arteries were harvested from young (33 = 7 yr, n ± 10), middle-aged (54 = 5 yr, n ± 10), and old (70 = 7 yr, n ± 10) subjects, and mitochondrial respiration as well as citrate synthase (CS) activity were assessed. Complex I (CI) and complex I < II (CI<II) state 3 respiration were greater in young (CI: 10.4 = 0.8 pmol·s‒1·mg‒1 and CI<II: 12.4 = 0.8 pmol·s‒1·mg‒1, P < 0.05) than middle-aged (CI: 7 = 0.6 pmol·s‒1·mg‒1 and CI<II: 8.3 = 0.5 pmol·s‒1·mg‒1) and old (CI: 7.2 = 0.4 pmol·s‒1·mg‒1 and CI<II: 7.6 = 0.5 pmol·s‒1·mg‒1) subjects and, as in the case of complex II (CII) state 3 respiration, were inversely correlated with age [r ±>0.56 (CI), r ±>0.7 (CI<II), and r ± 0.4 (CII), P < 0.05]. In contrast, state 4 respiration and mitochondria-specific superoxide levels were not different across groups. The respiratory control ratio was greater in young (2.2 = 0.2, P < 0.05) than middle-aged and old (1.4 = 0.1 and 1.1 = 0.1, respectively) subjects and inversely correlated with age (r ±>0.71, P < 0.05). As CS activity was inversely correlated with age (r ±>0.54, P < 0.05), when normalized for mitochondrial content, the age-related differences and relationships with state 3 respiration were ablated. In contrast, mitochondrion-specific state 4 respiration was now lower in young (15 = 1.4 pmol·s‒1·mg‒1·U CS‒1, P < 0.05) than middle-aged and old (23.4 = 3.6 and 27.9 = 3.4 pmol·s‒1·mg‒1·U CS‒1, respectively) subjects and correlated with age (r ± 0.46, P < 0.05). Similarly, superoxide/CS levels were lower in young (0.07 = 0.01) than old (0.19 = 0.41) subjects and correlated with age (r ± 0.44, P < 0.05). Therefore, with aging, vascular mitochondrial respiratory function declines, predominantly as a consequence of falling mitochondrial content. However, per mitochondrion, aging likely results in greater mitochondrion-derived oxidative stress, which may contribute to age-related vascular dysfunction. NEW & NOTEWORTHY This study determined, for the first time, that vascular mitochondrial oxidative respiratory capacity, oxidative coupling efficiency, and mitochondrial content fell progressively with advancing age. In terms of single mitochondrion-specific respiration, the age-related differences were completely ablated and the likelihood of free radical production increased progressively with advancing age. This study reveals that vascular mitochondrial respiratory capacity declines with advancing age, as a consequence of falling mitochondrial content, as does oxidative coupling efficiency.
KW - Mitochondrial content
KW - Proton leak
KW - Respiratory control ratio
KW - Skeletal muscle feed arteries
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U2 - 10.1152/ajpheart.00324.2018
DO - 10.1152/ajpheart.00324.2018
M3 - Article
C2 - 30192630
AN - SCOPUS:85060138093
VL - 315
SP - H1660-H1669
JO - American Journal of Physiology - Renal Physiology
JF - American Journal of Physiology - Renal Physiology
SN - 0363-6127
IS - 6
ER -