Overexpression of Catalase Targeted to Mitochondria Attenuates Murine Cardiac Aging

Dai, Dao Fu; Santana, Luis Fernando; Vermulst, Marc; Tomazela, Daniela M.; Emond, Mary J.; MacCoss, Michael J.; Gollahon, Katherine A.; Martin, George M.; Loeb, Lawrence A.; Ladiges, Warren; Rabinovitch, Peter S.

doi:10.1161/circulationaha.108.822403

Cited by 416 publications

(392 citation statements)

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“…Similar age-related changes have been described in mitochondrial mutator mice that carry a homozygous mutation in the catalytic subunit of mtDNA polymerase g (PolgA). 2,3 Interestingly, these changes were partially attenuated in mitochondrial mutator mice overexpressing catalase targeted to mitochondria (mCAT), 40 suggesting that mitochondrial ROS might play a role in these age-related changes.…”

Section: Discussionmentioning

confidence: 99%

Loss of HtrA2/Omi activity in non-neuronal tissues of adult mice causes premature aging

et al. 2012

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mnd2 mice die prematurely as a result of neurodegeneration 30-40 days after birth due to loss of the enzymatic activity of the mitochondrial quality control protease HtrA2/Omi. Here, we show that transgenic expression of human HtrA2/Omi in the central nervous system of mnd2 mice rescues them from neurodegeneration and prevents their premature death. Interestingly, adult transgenic mnd2 mice develop accelerated aging phenotypes, such as premature weight loss, hair loss, reduced fertility, curvature of the spine, heart enlargement, increased autophagy, and death by 12-17 months of age. These mice also have elevated levels of clonally expanded mitochondrial DNA (mtDNA) deletions in their tissues. Our results provide direct genetic evidence linking mitochondrial protein quality control to mtDNA deletions and aging in mammals. Cell Death and Differentiation (2013) 20, 259-269; doi:10.1038/cdd.2012 published online 14 September 2012 Mitochondria are dynamic organelles primarily involved in the production of adenosine triphosphate (ATP) through oxidative phosphorylation. They also play important roles in diverse cellular processes such as cell death, autophagy and innate immunity. 1 As a consequence of oxidative phosphorylation, mitochondria produce reactive oxygen species (ROS), which damages mitochondrial proteins, lipids and nucleic acids, because of their proximity to the source of ROS production. Accumulation over time of mutations and deletions in mitochondrial DNA (mtDNA) together with increased protein misfolding, as a result of ROS damage, leads to ageassociated decline in mitochondrial function, which is believed to be responsible for organismal aging and age-associated diseases. [2][3][4] To maintain optimal mitochondrial function over time, a number of quality control mechanisms exist that monitor and regulate all aspects of mitochondrial physiology. Damaged and unfolded mitochondrial proteins are removed by mitochondrial quality control proteases, which recognize these proteins and degrade them. 5,6 The ATP-dependent AAA (ATPase-Associated with diverse cellular Activities) proteases, are among the best-characterized proteases implicated in mitochondrial protein quality control. 7 The AAA proteases, ClpXP and Lon, located in the matrix are involved in quality control of matrix proteins. Although no specific mitochondrial substrate has been identified for the ClpXP protease, in vitro studies showed that Lon protease preferentially targets oxidatively damaged matrix aconitase. 8 Two additional AAA proteases, Paraplegin (encoded by the SPG7 gene) and YME1L, are associated with the inner membrane with their catalytic sites facing the matrix and intermembrane space, respectively. 7 These proteases are believed to be primarily involved in the degradation of damaged and unfolded membrane proteins of the electron transport chain. In addition, Paraplegin has been shown to process the mitochondrial ribosomal protein MrpL32, 9 suggesting that it might also function in mitochondrial ribosome assembly. Loss-of-functi...

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Section: Discussionmentioning

confidence: 99%

Loss of HtrA2/Omi activity in non-neuronal tissues of adult mice causes premature aging

et al. 2012

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“…For mice from all genotypes or treatment groups, anesthesia was induced with 2% isoflurane and sustained with 0.5% isoflurane. Echocardiography was performed with an Acuson CV-70 cardiovascular ultrasound system (Siemens) using standard imaging planes: M-mode, conventional and Tissue Doppler imaging as described previously (54). To test the effect of persistent β-adrenergic stimulation, 3-moold SA mice and age-matched WT mice were injected i.p.…”

Section: Methodsmentioning

confidence: 99%

Loss of β-adrenergic–stimulated phosphorylation of Ca _V 1.2 channels on Ser1700 leads to heart failure

Yang

Dai

Yuan

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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L-type Ca 2+ currents conducted by voltage-gated calcium channel 1.2 (Ca V 1.2) initiate excitation-contraction coupling in the heart, and altered expression of Ca V 1.2 causes heart failure in mice. Here we show unexpectedly that reducing β-adrenergic regulation of Ca V 1.2 channels by mutation of a single PKA site, Ser1700, in the proximal C-terminal domain causes reduced contractile function, cardiac hypertrophy, and heart failure without changes in expression, localization, or function of the Ca V 1.2 protein in the mutant mice (SA mice). These deficits were aggravated with aging. Dual mutation of Ser1700 and a nearby casein-kinase II site (Thr1704) caused accelerated hypertrophy, heart failure, and death in mice with these mutations (STAA mice). Cardiac hypertrophy was increased by voluntary exercise and by persistent β-adrenergic stimulation. PKA expression was increased, and PKA sites Ser2808 in ryanodine receptor type-2, Ser16 in phospholamban, and Ser23/24 in troponin-I were hyperphosphorylated in SA mice, whereas phosphorylation of substrates for calcium/calmodulin-dependent protein kinase II was unchanged. The Ca 2+ pool in the sarcoplasmic reticulum was increased, the activity of calcineurin was elevated, and calcineurin inhibitors improved contractility and ameliorated cardiac hypertrophy. Cardio-specific expression of the SA mutation also caused reduced contractility and hypertrophy. These results suggest engagement of compensatory mechanisms, which initially may enhance the contractility of individual myocytes but eventually contribute to an increased sensitivity to cardiovascular stress and to heart failure in vivo. Our results demonstrate that normal regulation of Ca V 1.2 channels by phosphorylation of Ser1700 in cardiomyocytes is required for cardiovascular homeostasis and normal physiological regulation in vivo.calcium channel | heart failure | excitation-contraction coupling | PKA | casein kinase II E xcitation-contraction (EC) coupling in the heart is initiated by L-type calcium (Ca 2+ ) currents conducted by voltagegated calcium 1.2 (Ca V 1.2) channels that are activated by membrane depolarization (1). Ca 2+ influx via Ca V 1.2 channels activates Ca 2+ release from the sarcoplasmic reticulum (SR), leading to rapid and forceful contraction of myofilaments. Ryanodine receptor type-2 (RyR2) is the major channel for this release of Ca 2+ from cardiac SR (2, 3). Mobilized Ca 2+ is transported back into the SR by the SR Ca 2+ ATPase (SERCA) during muscle relaxation (4). SERCA activity is controlled by the inhibitor protein phospholamban (PLB), which is phosphorylated by PKA to release its inhibition of SERCA activity (4). The force and rate of cardiac contractions are critically dependent on the amplitude and kinetics of the Ca 2+ signal generated by Ca V 1.2 channels and RyR2 (1). In the fight-or-flight response, a marked increase in the beating rate and force of contraction of the heart is triggered by activation of the sympathetic nervous system and stimulation of the β-adrenergic signaling p...

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“…MCAT Mice Develop Less Severe Age-related OA-Previous studies have demonstrated increased longevity and a reduction in age-related pathology in mice expressing catalase targeted to the mitochondria, in part because of decreased H 2 O 2 production, attenuation of oxidative stress-induced damage, and maintenance of mitochondrial homeostasis (43,44). To investigate whether MCAT mice are protected from age-associated OA, we assessed knee joints that had been previously collected from 18 -33-month-old male MCAT and wild-type mice.…”

Section: Menadione-induced Prx Hyperoxidation and P38 Phosphorylationmentioning

confidence: 99%

Oxidative Stress Promotes Peroxiredoxin Hyperoxidation and Attenuates Pro-survival Signaling in Aging Chondrocytes

Collins

Wood

Nelson

et al. 2016

Journal of Biological Chemistry

106

108

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Oxidative stress-mediated post-translational modifications of redox-sensitive proteins are postulated as a key mechanism underlying age-related cellular dysfunction and disease progression. Peroxiredoxins (PRX) are critical intracellular antioxidants that also regulate redox signaling events. Age-related osteoarthritis is a common form of arthritis that has been associated with mitochondrial dysfunction and oxidative stress. The objective of this study was to determine the effect of aging and oxidative stress on chondrocyte intracellular signaling, with a specific focus on oxidation of cytosolic PRX2 and mitochondrial PRX3. Menadione was used as a model to induce cellular oxidative stress. Compared with chondrocytes isolated from young adult humans, chondrocytes from older adults exhibited higher levels of PRX1-3 hyperoxidation basally and under conditions of oxidative stress. Peroxiredoxin hyperoxidation was associated with inhibition of pro-survival Akt signaling and stimulation of pro-death p38 signaling. These changes were prevented in cultured human chondrocytes by adenoviral expression of catalase targeted to the mitochondria (MCAT) and in cartilage explants from MCAT transgenic mice. Peroxiredoxin hyperoxidation was observed in situ in human cartilage sections from older adults and in osteoarthritic cartilage. MCAT transgenic mice exhibited less age-related osteoarthritis. These findings demonstrate that age-related oxidative stress can disrupt normal physiological signaling and contribute to osteoarthritis and suggest peroxiredoxin hyperoxidation as a potential mechanism.Aging is characterized by an inability to maintain homeostasis resulting in a progressive loss of function and is associated with many chronic conditions including cancer, type II diabetes, neurodegenerative disease, cardiovascular disease, and osteoarthritis (1, 2). Although several theories aimed at explaining the aging phenotype have been suggested, an age-related imbalance between the production of reactive oxygen species (ROS) 2 and the antioxidant capacity of the cell has been identified as a contributing factor (3-5). Although the original free radical theory of aging focused on accumulation of cellular damage from excessive ROS as a cause for aging and age-related conditions, more recent studies suggest that disturbances in redox signaling that result from age-related oxidative stress are likely to play a key role (5-7). Increased levels of ROS caused by mitochondrial dysfunction, one of the hallmarks of aging, have been proposed to contribute to age-related oxidative stress, but the underlying mechanisms for how this increase causes a disruption in cell signaling leading to cell and tissue dysfunction is poorly understood (1, 4, 8).Recent advances in redox signaling recognize that reversible post-translational oxidative modifications of reactive protein cysteine thiols mediated by controlled production of H 2 O 2 regulate key signal transduction events (9, 10). The cysteine-dependent peroxiredoxins (PRXs), which display high rea...

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Overexpression of Catalase Targeted to Mitochondria Attenuates Murine Cardiac Aging

Cited by 416 publications

References 33 publications

Loss of HtrA2/Omi activity in non-neuronal tissues of adult mice causes premature aging

Loss of HtrA2/Omi activity in non-neuronal tissues of adult mice causes premature aging

Loss of β-adrenergic–stimulated phosphorylation of Ca _V 1.2 channels on Ser1700 leads to heart failure

Oxidative Stress Promotes Peroxiredoxin Hyperoxidation and Attenuates Pro-survival Signaling in Aging Chondrocytes

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Overexpression of Catalase Targeted to Mitochondria Attenuates Murine Cardiac Aging

Cited by 416 publications

References 33 publications

Loss of HtrA2/Omi activity in non-neuronal tissues of adult mice causes premature aging

Loss of HtrA2/Omi activity in non-neuronal tissues of adult mice causes premature aging

Loss of β-adrenergic–stimulated phosphorylation of Ca V 1.2 channels on Ser1700 leads to heart failure

Oxidative Stress Promotes Peroxiredoxin Hyperoxidation and Attenuates Pro-survival Signaling in Aging Chondrocytes

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Product

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Loss of β-adrenergic–stimulated phosphorylation of Ca _V 1.2 channels on Ser1700 leads to heart failure