Rapamycin transiently induces mitochondrial remodeling to reprogram energy metabolism in old hearts

Chiao, Ying Ann; Kolwicz, Stephen C.; Basisty, Nathan; Gagnidze, Arni; Zhang, Julia; Gu, Haiwei; Djukovic, Danijel; Beyer, Richard P.; Raftery, Daniel; MacCoss, Michael J.; Tian, Rong; Rabinovitch, Peter S.

doi:10.18632/aging.100881

Cited by 87 publications

(59 citation statements)

References 40 publications

(59 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Also, both THs decreased mTORC1/2, whose inhibition is involved in mitochondrial biogenesis and reportedly restores a more juvenile phenotype and increased life span (Chiao et al, 2016;Evangelisti et al, 2016;Johnson et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…we investigated the effect of THs on the transcription of sirtuin-1 (sirt1), which is associated with lifespan expansion in common laboratory species, regulates senescence, aging, genomic stability and mitochondrial homeostasis (Fang et al, 2016;Hayakawa et al, 2015;Poulose and Raju, 2015), and the sirt1 target, PGC1α, a central regulator of aging, which enhances mitochondrial biogenesis and controls oxidative stress by up-regulating important ROS scavengers (Austin and St-Pierre, 2012;Gilbert, 2013;Riera and Dillin, 2015;Wenz, 2011). Finally, we quantified the cyclin-dependent kinase inhibitor 2A, multiple tumor suppressor 1 (p16 ink4a ), a key cell cycle senescence biomarker (Baker et al, 2011) and the mammalian target of rapamycin (mTORC1/2), another key regulator of ageing (Chiao et al, 2016;Evangelisti et al, 2016;Johnson et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Thyroid Hormones Enhance Mitochondrial Function in Human Epidermis

Vidali

Chéret

Giesen

et al. 2016

Journal of Investigative Dermatology

View full text Add to dashboard Buy / Rent full text

Since it is unknown whether thyroid hormones (THs) regulate mitochondrial function in human epidermis, we treated organ-cultured human skin, or isolated cultured human epidermal keratinocytes, with triiodothyronine (100 pmol/L) or thyroxine (100 nmol/L). Both THs significantly increased protein expression of the mitochondrially encoded cytochrome C oxidase I (MTCO1), complex I activity, and the number of perinuclear mitochondria. Triiodothyronine also increased mitochondrial transcription factor A (TFAM) protein expression, and thyroxine stimulated complex II/IV activity. Increased mitochondrial function can correlate with increased reactive oxygen species production, DNA damage, and accelerated tissue aging. However, THs neither raised reactive oxygen species production or matrix metalloproteinase-1, -2 and -9 activity nor decreased sirtuin1 (Sirt1) immunoreactivity. Instead, triiodothyronine increased sirtuin-1, fibrillin-1, proliferator-activated receptor-gamma 1-alpha (PGC1α), collagen I and III transcription, and thyroxine decreased cyclin-dependent kinase inhibitor 2A (p16(ink4)) expression in organ-cultured human skin. Moreover, TH treatment increased intracutaneous fibrillin-rich microfibril and collagen III deposition and decreased mammalian target of rapamycin (mTORC1/2) expression ex vivo. This identifies THs as potent endocrine stimulators of mitochondrial function in human epidermis, which down-regulates rather than enhance the expression of skin aging-related biomarkers ex vivo. Therefore, topically applied THs deserve further exploration as candidate agents for treating skin conditions characterized by reduced mitochondrial function.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Thyroid Hormones Enhance Mitochondrial Function in Human Epidermis

Vidali

Chéret

Giesen

et al. 2016

Journal of Investigative Dermatology

View full text Add to dashboard Buy / Rent full text

show abstract

“…Fatty acid oxidation is decreased in the aging heart. 9, 10 PDK4 content is decreased in the aged heart, 9 favoring increased glucose oxidation at the expense of fatty acid oxidation.…”

Section: Metabolism and Metabolic Flexibility In The Aging Heartmentioning

confidence: 96%

“…241 In aged female C57BL/6 mice, rapamycin feeding for 10 weeks transiently induces autophagy, increases mitochondrial biogenesis, improves energy metabolism, especially fatty acid metabolism, and alters the myocardial metabolome. 10 Rapamycin therapy started even late in life exerted beneficial effects in cardiac function and cardiac gene and protein expression. 242, 243 The response to superimposed stress of ischemia-reperfusion or heart failure remains an area of major interest.…”

Section: Harnessing the Mitochondria: Treatment Of Age-enhanced Cmentioning

confidence: 99%

Mitochondrial Metabolism in Aging Heart

2016

View full text Add to dashboard Buy / Rent full text

Altered mitochondrial metabolism is the underlying basis for the increased sensitivity in the aged heart to stress. The aged heart exhibits impaired metabolic flexibility, with a decreased capacity to oxidize fatty acids and enhanced dependence on glucose metabolism. Aging impairs mitochondrial oxidative phosphorylation, with a greater role played by the mitochondria located between the myofibrils, the interfibrillar mitochondria. With aging, there is a decrease in activity of complexes III and IV, which account for the decrease in respiration. Furthermore, aging decreases mitochondrial content among the myofibrils. The end result is that in the interfibrillar area there is an approximate 50% decrease in mitochondrial function, affecting all substrates. The defective mitochondria persist in the aged heart, leading to enhanced oxidant production and oxidative injury and the activation of oxidant signaling for cell death. Aging defects in mitochondria represent new therapeutic targets, whether by manipulation of the mitochondrial proteome, modulation of electron transport, activation of biogenesis or mitophagy, or the regulation of mitochondrial fission and fusion. These mechanisms provide new ways to attenuate cardiac disease in elders by preemptive treatment of age-related defects, in contrast to the treatment of disease-induced dysfunction.

show abstract

“…143, 154 Nonselective beta-adrenergic receptor agonists isoproterenol and norepinephrine as well as the selective beta2 adrenergic receptor agonist salbutamol were reported to increase autophagic flux which was blocked by propranolol. 155 Confusingly, it has also been reported that the beta-blocker propranolol 156 stimulates autophagy.…”

Section: Interventional Potentialmentioning

confidence: 99%

Myocardial stress and autophagy: mechanisms and potential therapies

et al. 2017

View full text Add to dashboard Buy / Rent full text

Autophagy is a ubiquitous cellular catabolic process responsive to energy stress status. Research over the last decade has revealed that cardiomyocyte autophagy is a prominent homeostatic pathway, important in adaptation to altered myocardial metabolic demand. The cellular machinery of autophagy involves targeted direction of macromolecules and organelles for lysosomal degradation. Autophagy activation has been identified as cardio-protective in some settings (i.e. ischemia and ischemic preconditioning). In other situations chronically elevated levels of autophagy have been linked with cardiopathology (i.e. sustained pressure overload and failure). Autophagy perturbation in diabetic cardiomyopathy is also observed – and has been associated with both adaptive and maladaptive stress responses. Recent findings indicate that various forms of selective autophagy operate in parallel to manage different catabolic ‘cargo’ types including mitochondria, large proteins, glycogen and lipid stores. In this Review, specific circumstances of autophagy induction associated with cardiac benefit or detriment are considered. The various static and dynamic approaches used for measurement of autophagy are critiqued and current inconsistencies in the understanding of autophagy regulation in the heart are highlighted. The future prospects for pharmacological intervention to achieve therapeutic manipulation of autophagic processes are canvassed.

show abstract

Rapamycin transiently induces mitochondrial remodeling to reprogram energy metabolism in old hearts

Cited by 87 publications

References 40 publications

Thyroid Hormones Enhance Mitochondrial Function in Human Epidermis

Thyroid Hormones Enhance Mitochondrial Function in Human Epidermis

Mitochondrial Metabolism in Aging Heart

Myocardial stress and autophagy: mechanisms and potential therapies

Contact Info

Product

Resources

About