Mitochondrial quality control mechanisms as molecular targets in cardiac ageing

Abstract

Cardiovascular disease is the leading cause of morbidity and mortality worldwide. Advancing age is a major risk factor for developing cardiovascular disease because of the lifelong exposure to cardiovascular risk factors and specific alterations affecting the heart and the vasculature during ageing. Indeed, the ageing heart is characterized by structural and functional changes that are caused by alterations in fundamental cardiomyocyte functions. In particular, the myocardium is heavily dependent on mitochondrial oxidative metabolism and is especially susceptible to mitochondrial dysfunction. Indeed, primary alterations in mitochondrial function, which are subsequently amplified by defective quality control mechanisms, are considered to be major contributing factors to cardiac senescence. In this Review, we discuss the mechanisms linking defective mitochondrial quality control mechanisms (that is, proteostasis, biogenesis, dynamics, and autophagy) to organelle dysfunction in the context of cardiac ageing. We also illustrate relevant molecular pathways that might be exploited for the prevention and treatment of age-related heart dysfunction.

Key points

  • Older adults are especially vulnerable to developing cardiovascular disease owing to long-term exposure to risk factors and intrinsic cardiovascular alterations occurring during ageing.

  • Mitochondrial quality control (MQC) operates through the coordination of various processes (proteostasis, biogenesis, dynamics, and mitophagy) to ensure cell homeostasis.

  • Mitochondrial dysfunction, amplified by failing quality control processes, is believed to be a major mechanism underlying cardiac ageing and cardiovascular disease.

  • Preclinical evidence suggests that modulation of MQC can be harnessed for therapeutic benefit against cardiac ageing and cardiovascular disease.

  • Current unknowns include the optimal window of MQC functioning to achieve cardioprotection, the timing and intensity of interventions, and noninvasively accessible biomarkers of MQC in the heart.

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Fig. 1: Mitochondrial quality control pathways.
Fig. 2: Nucleus–mitochondrion crosstalk during cardiac ageing.
Fig. 3: Regulation of cardiac autophagy.

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Acknowledgements

The authors acknowledge support from Fondazione Roma (NCDs Call for Proposals 2013), Innovative Medicine Initiative-Joint Undertaking (IMI-JU 115621), intramural research grants from the Catholic University of the Sacred Heart (D3.2 2013 and D3.2 2015), the non-profit research foundation “Centro Studi Achille e Linda Lorenzon”, and the Claude D. Pepper Older Americans Independence Center at the University of Florida’s Institute on Aging (NIA 1P30AG028740).

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Nature Reviews Cardiology thanks E. Lesnefsky and the other anonymous reviewers for their contribution to the peer review of this work.

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A.P. and R.T.M. researched data for the article. A.P., J.L.B., and J.-S.K. discussed the content of the article. A.P., R.T.M., L.D., and E.M. wrote the manuscript. E.M. and C.L. revised and edited the manuscript before submission.

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Correspondence to Emanuele Marzetti or Christiaan Leeuwenburgh.

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Picca, A., Mankowski, R.T., Burman, J.L. et al. Mitochondrial quality control mechanisms as molecular targets in cardiac ageing. Nat Rev Cardiol 15, 543–554 (2018). https://doi.org/10.1038/s41569-018-0059-z

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