Is Mitochondrial Dysfunction a Common Root of Noncommunicable Chronic Diseases?

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Abstract

Mitochondrial damage is implicated as a major contributing factor for a number of noncommunicable chronic diseases such as cardiovascular diseases, cancer, obesity, and insulin resistance/type 2 diabetes. Here, we discuss the role of mitochondria in maintaining cellular and whole-organism homeostasis, the mechanisms that promote mitochondrial dysfunction, and the role of this phenomenon in noncommunicable chronic diseases. We also review the state of the art regarding the preclinical evidence associated with the regulation of mitochondrial function and the development of current mitochondria-targeted therapeutics to treat noncommunicable chronic diseases. Finally, we give an integrated vision of how mitochondrial damage is implicated in these metabolic diseases.

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Most cited references 184

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AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha.

Sibylle Jager, Christoph Handschin, Julie St-Pierre … (2007)

Activation of AMP-activated kinase (AMPK) in skeletal muscle increases glucose uptake, fatty acid oxidation, and mitochondrial biogenesis by increasing gene expression in these pathways. However, the transcriptional components that are directly targeted by AMPK are still elusive. The peroxisome-proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) has emerged as a master regulator of mitochondrial biogenesis; furthermore, it has been shown that PGC-1alpha gene expression is induced by exercise and by chemical activation of AMPK in skeletal muscle. Using primary muscle cells and mice deficient in PGC-1alpha, we found that the effects of AMPK on gene expression of glucose transporter 4, mitochondrial genes, and PGC-1alpha itself are almost entirely dependent on the function of PGC-1alpha protein. Furthermore, AMPK phosphorylates PGC-1alpha directly both in vitro and in cells. These direct phosphorylations of the PGC-1alpha protein at threonine-177 and serine-538 are required for the PGC-1alpha-dependent induction of the PGC-1alpha promoter. These data indicate that AMPK phosphorylation of PGC-1alpha initiates many of the important gene regulatory functions of AMPK in skeletal muscle.

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Mitochondrial Machineries for Protein Import and Assembly.

Nils Wiedemann, Nikolaus Pfanner (2017)

Mitochondria are essential organelles with numerous functions in cellular metabolism and homeostasis. Most of the >1,000 different mitochondrial proteins are synthesized as precursors in the cytosol and are imported into mitochondria by five transport pathways. The protein import machineries of the mitochondrial membranes and aqueous compartments reveal a remarkable variability of mechanisms for protein recognition, translocation, and sorting. The protein translocases do not operate as separate entities but are connected to each other and to machineries with functions in energetics, membrane organization, and quality control. Here, we discuss the versatility and dynamic organization of the mitochondrial protein import machineries. Elucidating the molecular mechanisms of mitochondrial protein translocation is crucial for understanding the integration of protein translocases into a large network that controls organelle biogenesis, function, and dynamics.

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Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study.

Julie A. Mattison, George Roth, T. Beasley … (2012)

Calorie restriction (CR), a reduction of 10–40% in intake of a nutritious diet, is often reported as the most robust non-genetic mechanism to extend lifespan and healthspan. CR is frequently used as a tool to understand mechanisms behind ageing and age-associated diseases. In addition to and independently of increasing lifespan, CR has been reported to delay or prevent the occurrence of many chronic diseases in a variety of animals. Beneficial effects of CR on outcomes such as immune function, motor coordination and resistance to sarcopenia in rhesus monkeys have recently been reported. We report here that a CR regimen implemented in young and older age rhesus monkeys at the National Institute on Aging (NIA) has not improved survival outcomes. Our findings contrast with an ongoing study at the Wisconsin National Primate Research Center (WNPRC), which reported improved survival associated with 30% CR initiated in adult rhesus monkeys (7–14 years) and a preliminary report with a small number of CR monkeys. Over the years, both NIA and WNPRC have extensively documented beneficial health effects of CR in these two apparently parallel studies. The implications of the WNPRC findings were important as they extended CR findings beyond the laboratory rodent and to a long-lived primate. Our study suggests a separation between health effects, morbidity and mortality, and similar to what has been shown in rodents, study design, husbandry and diet composition may strongly affect the life-prolonging effect of CR in a long-lived nonhuman primate.

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Author and article information

Journal

Title: Endocrine Reviews

Publisher: The Endocrine Society

ISSN (Print): 0163-769X

ISSN (Electronic): 1945-7189

Publication date Created: June 2020

Publication date Created: June 01 2020

Publication date Other: June 2020

Publication date (Print): June 01 2020

Publication date (Electronic): March 16 2020

Volume: 41

Issue: 3

Affiliations

[1 ]Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile

[2 ]Charles Perkins Centre, School of Life and Environmental Sciences, The University of Sydney, Camperdown, Sydney, NSW, Australia

[3 ]Institute of Nutrition and Food Technology (INTA), Universidad de Chile, Santiago, Chile

[4 ]Center for Studies of Exercise, Metabolism and Cancer (CEMC), Facultad de Medicina, Universidad de Chile, Santiago, Chile

[5 ]Department of Internal Medicine (Cardiology Division), University of Texas Southwestern Medical Center, Dallas, Texas

Article

DOI: 10.1210/endrev/bnaa005

SO-VID: 918e8117-c076-447a-acf5-3503bea55f3f

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https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model

Is Mitochondrial Dysfunction a Common Root of Noncommunicable Chronic Diseases?

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Genes & Diseases

Most cited references 184

AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha.

Mitochondrial Machineries for Protein Import and Assembly.

Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study.

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