Mitochondrial genetic background modulates bioenergetics and susceptibility to acute cardiac volume overload

Fetterman, Joseph L.; Zelickson, B. R.; Johnson, L. W.; Moellering, Douglas R.; Westbrook, David G.; Pompilius, M.; Sammy, M. J.; Johnson, M.; Dunham-Snary, K. J.; Cao, X.; Bradley, W. E.; Zhang, J.; Wei, C.-C.; Chacko, B.; Schurr, T. G.; Kesterson, Robert A.; Dell’italia, L. J.; Darley-Usmar, V. M.; Welch, Danny R.; Ballinger, Scott W.

doi:10.1042/bj4560147

Cited by 9 publications

(11 citation statements)

References 27 publications

(27 reference statements)

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“…To determine the effects of MitoQ on cardiomyocyte bioenergetics, the Seahorse Bioscience XF24 extracellular flux analyzer was used to measure the O 2 consumption of adult cardiomyocytes in culture (16,18). The O2 consumption rate (OCR) was related to mitochondrial function using the mitochondrial stress test (16).…”

Section: Controlmentioning

confidence: 99%

Cardiomyocyte mitochondrial oxidative stress and cytoskeletal breakdown in the heart with a primary volume overload

Yancey

Guichard

Ahmed

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Left ventricular (LV) volume overload (VO) results in cardiomyocyte oxidative stress and mitochondrial dysfunction. Because mitochondria are both a source and target of ROS, we hypothesized that the mitochondrially targeted antioxidant mitoubiquinone (MitoQ) will improve cardiomyocyte damage and LV dysfunction in VO. Isolated cardiomyocytes from Sprague-Dawley rats were exposed to stretch in vitro and VO of aortocaval fistula (ACF) in vivo. ACF rats were treated with and without MitoQ. Isolated cardiomyocytes were analyzed after 3 h of cyclical stretch or 8 wk of ACF with MitoSox red or 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate to measure ROS and with tetramethylrhodamine to measure mitochondrial membrane potential. Transmission electron microscopy and immunohistochemistry were used for cardiomyocyte structural assessment. In vitro cyclical stretch and 8-wk ACF resulted in increased cardiomyocyte mitochondrial ROS production and decreased mitochondrial membrane potential, which were significantly improved by MitoQ. ACF had extensive loss of desmin and β₂-tubulin that was paralleled by mitochondrial disorganization, loss of cristae, swelling, and clustering identified by mitochondria complex IV staining and transmission electron microscopy. MitoQ improved mitochondrial structural damage and attenuated desmin loss/degradation evidenced by immunohistochemistry and protein expression. However, LV dilatation and fractional shortening were unaffected by MitoQ treatment in 8-wk ACF. In conclusion, although MitoQ did not affect LV dilatation or function in ACF, these experiments suggest a connection of cardiomyocyte mitochondria-derived ROS production with cytoskeletal disruption and mitochondrial damage in the VO of ACF.

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Section: Controlmentioning

confidence: 99%

Cardiomyocyte mitochondrial oxidative stress and cytoskeletal breakdown in the heart with a primary volume overload

Yancey

Guichard

Ahmed

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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“…In mice, mt-n epistasis is known to affect cognition (Roubertoux et al 2003), ROS (Fetterman et al 2013), and respiratory functions (Betancourt et al 2014) as well as tissuespecific selection for mtDNA variants (Jenuth et al 1997). Interactions between mt and n genomes likely contribute to cytoplasmic male sterility in plants (Hu et al 2014) and disease presentation and aging in humans (Tranah 2011;Wallace and Chalkia 2013;Wolff et al 2014), suggesting that mt-n epistasis is important in most eukaryotes.…”

mentioning

confidence: 99%

Mitochondrial-Nuclear Epistasis Contributes to Phenotypic Variation and Coadaptation in Natural Isolates of Saccharomyces cerevisiae

Paliwal¹,

Fiumera²,

Fiumera

2014

Genetics

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Mitochondria are essential multifunctional organelles whose metabolic functions, biogenesis, and maintenance are controlled through genetic interactions between mitochondrial and nuclear genomes. In natural populations, mitochondrial efficiencies may be impacted by epistatic interactions between naturally segregating genome variants. The extent that mitochondrial-nuclear epistasis contributes to the phenotypic variation present in nature is unknown. We have systematically replaced mitochondrial DNAs in a collection of divergent Saccharomyces cerevisiae yeast isolates and quantified the effects on growth rates in a variety of environments. We found that mitochondrial-nuclear interactions significantly affected growth rates and explained a substantial proportion of the phenotypic variances under some environmental conditions. Naturally occurring mitochondrial-nuclear genome combinations were more likely to provide growth advantages, but genetic distance could not predict the effects of epistasis. Interruption of naturally occurring mitochondrial-nuclear genome combinations increased endogenous reactive oxygen species in several strains to levels that were not always proportional to growth rate differences. Our results demonstrate that interactions between mitochondrial and nuclear genomes generate phenotypic diversity in natural populations of yeasts and that coadaptation of intergenomic interactions likely occurs quickly within the specific niches that yeast occupy. This study reveals the importance of considering allelic interactions between mitochondrial and nuclear genomes when investigating evolutionary relationships and mapping the genetic basis underlying complex traits. M ITOCHONDRIAL energy production, which affects virtually every aspect of cellular fitness, requires the participation of two genomes. The mitochondrial genome encodes for essential components of the oxidative phosphorylation machinery and mitochondrial ribosomal RNAs and transfer RNAs. The nuclear genome encodes nearly 1000 proteins that are imported to the organelle where they compose the majority of the mitochondrial proteome. Specific interactions between components of both genomes are required at many levels, including mitochondrial DNA (mtDNA) replication, repair, and inheritance and transcription, translation, and assembly of the electron transport chain components. The respiratory complexes themselves are heterogeneous, composed of both nuclear and mitochondrially encoded proteins. Over evolutionary time, these interactions have been optimized, in part, to regulate production of the reactive oxygen species (ROS) that are the by-products of mitochondrial respiration.Allelic variation in both genomes can affect mt-n interactions and alter mitochondrial fitness. These interactions have been shown to have direct consequences on healthrelated and life-history phenotypes in several taxa. In insects such as Drosophila and Callosobruchus (seed beetle), exchanging mtDNA variants between distinct populations has led to lowered metabo...

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“…[20][21][22] Interestingly, among the 13 proteins coded for by the mtDNA are the critical redox centers in the respiratory chain, which offer a mechanism through which mutations in mtDNA could modulate superoxide levels in response to stress and, thus, impact on pathological processes. [23] Taken together, these findings result in the new field of redox bioenergetics.…”

Section: The Emerging Theme Of Redox Bioenergetics In Health and Diseasementioning

confidence: 96%

“…Interestingly, it is now becoming clear that the mitochondrial genetic background is capable of conferring resistance or suceptability to cardiovascular disease by modulating redox signaling. [23] One concept that is gaining acceptance is that it is the modulation of the mitochondrial protein thiol networks which are an essential intermediate in retrograde signaling pathways. [41] Interestingly, except in some specialized cases, protein thiols are not very reactive with hydrogen peroxide.…”

Section: Mechanisms Of Mitochondrial Reactive Oxygen Species and Thermentioning

confidence: 99%

The emerging theme of redox bioenergetics in health and disease

Kramer¹,

Darley‐Usmar²

2015

Biomed J

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Mitochondrial genetic background modulates bioenergetics and susceptibility to acute cardiac volume overload

Cited by 9 publications

References 27 publications

Cardiomyocyte mitochondrial oxidative stress and cytoskeletal breakdown in the heart with a primary volume overload

Cardiomyocyte mitochondrial oxidative stress and cytoskeletal breakdown in the heart with a primary volume overload

Mitochondrial-Nuclear Epistasis Contributes to Phenotypic Variation and Coadaptation in Natural Isolates of Saccharomyces cerevisiae

The emerging theme of redox bioenergetics in health and disease

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