Mitochondrial Dynamics in the Regulation of Nutrient Utilization and Energy Expenditure

Department of Medicine, Obesity and Nutrition Section, Mitochondria ARC, Evans Biomedical Research Center, Boston University School of Medicine, 650 Albany Street, Boston, MA 02118, USA.
Cell metabolism (Impact Factor: 17.57). 04/2013; 17(4):491-506. DOI: 10.1016/j.cmet.2013.03.002
Source: PubMed


Mitochondrial fusion, fission, and mitophagy form an essential axis of mitochondrial quality control. However, quality control might not be the only task carried out by mitochondrial dynamics. Recent studies link mitochondrial dynamics to the balance between energy demand and nutrient supply, suggesting changes in mitochondrial architecture as a mechanism for bioenergetic adaptation to metabolic demands. By favoring either connected or fragmented architectures, mitochondrial dynamics regulates bioenergetic efficiency and energy expenditure. Placement of bioenergetic adaptation and quality control as competing tasks of mitochondrial dynamics might provide a new mechanism, linking excess nutrient environment to progressive mitochondrial dysfunction, common to age-related diseases.

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    • "While the rhythmic mitochondrial remodeling in vivo is dependent on diurnal Bmal1 activity and independent of substrate availability, the mitochondrial network could be manipulated by altering nutrient conditions in cultured hepatocytes. As reported previously for b cells (Liesa and Shirihai, 2013; Molina et al., 2009), the mitochondrial network of WT hepatocytes could be ''reset'' to a fused or elongated morphology in EBSS, followed by a fragmented morphology when switching to HG+PA. LBmal1KO mitochondria lack these adaptations and retain the swollen morphology. "
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    ABSTRACT: Mitochondria undergo architectural/functional changes in response to metabolic inputs. How this process is regulated in physiological feeding/fasting states remains unclear. Here we show that mitochondrial dynamics (notably fission and mitophagy) and biogenesis are transcriptional targets of the circadian regulator Bmal1 in mouse liver and exhibit a metabolic rhythm in sync with diurnal bioenergetic demands. Bmal1 loss-of-function causes swollen mitochondria incapable of adapting to different nutrient conditions accompanied by diminished respiration and elevated oxidative stress. Consequently, liver-specific Bmal1 knockout (LBmal1KO) mice accumulate oxidative damage and develop hepatic insulin resistance. Restoration of hepatic Bmal1 activities in high-fat-fed mice improves metabolic outcomes, whereas expression of Fis1, a fission protein that promotes quality control, rescues morphological/metabolic defects of LBmal1KO mitochondria. Interestingly, Bmal1 homolog AHA-1 in C. elegans retains the ability to modulate oxidative metabolism and lifespan despite lacking circadian regulation. These results suggest clock genes are evolutionarily conserved energetics regulators.
    Cell metabolism 09/2015; 22(4). DOI:10.1016/j.cmet.2015.08.006 · 17.57 Impact Factor
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    • "The homeostatic control of energy metabolism includes multiple organs and pathways that sense and transduce environmental stimuli into adaptive responses. Mitochondria play an integral role in this rapid adaptation to varying nutrient substrates and bioenergetic demand by forming interwebbed mitochondrial networks, which are reshaped dynamically by fusion and fission events (Liesa and Shirihai, 2013). Mitochondrial fusion, governed by enzymes such as mitofusin 1/2 and optic atrophy factor 1 (OPA1), mitigates cellular stress by distributing damaged mitochondrial content over a wider compartment. "
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    ABSTRACT: Canonical protein phosphatase 3/calcineurin signaling is central to numerous physiological processes. Here we provide evidence that calcineurin plays a pivotal role in controlling systemic energy and body weight homeostasis. Knockdown of calcineurin in Drosophila melanogaster led to a decrease in body weight and energy stores, and increased energy expenditure. In mice, global deficiency of catalytic subunit Ppp3cb, and tissue-specific ablation of regulatory subunit Ppp3r1 from skeletal muscle, but not adipose tissue or liver, led to protection from high-fat-diet-induced obesity and comorbid sequelæ. Ser637 hyperphosphorylation of dynamin-related protein 1 (Drp1) in skeletal muscle of calcineurin-deficient mice was associated with mitochondrial elongation into power-cable-shaped filaments and increased mitochondrial respiration, but also with attenuated exercise performance. Our data suggest that calcineurin acts as highly conserved pivot for the adaptive metabolic responses to environmental changes such as high-fat, high-sugar diets or exercise.
    Cell metabolism 09/2015; DOI:10.1016/j.cmet.2015.08.022 · 17.57 Impact Factor
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    • "One key factor in the regulation of mitochondrial function is mitochondrial dynamics (Gao et al., 2014). Healthy mitochondrial dynamics consist of repeated cycles of mitochondrial fusion and fission and are coupled to mitochondrial breakdown through mitophagy (Andreux et al., 2013; Gao et al., 2014; Liesa and Shirihai, 2013; Youle and van der Bliek, 2012). We previously showed that inhibiting mitochondrial translation promotes mitochondrial fission in worms (Houtkooper et al., 2013). "
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    ABSTRACT: In recent years, tetracyclines, such as doxycycline, have become broadly used to control gene expression by virtue of the Tet-on/Tet-off systems. However, the wide range of direct effects of tetracycline use has not been fully appreciated. We show here that these antibiotics induce a mitonuclear protein imbalance through their effects on mitochondrial translation, an effect that likely reflects the evolutionary relationship between mitochondria and proteobacteria. Even at low concentrations, tetracyclines induce mitochondrial proteotoxic stress, leading to changes in nuclear gene expression and altered mitochondrial dynamics and function in commonly used cell types, as well as worms, flies, mice, and plants. Given that tetracyclines are so widely applied in research, scientists should be aware of their potentially confounding effects on experimental results. Furthermore, these results caution against extensive use of tetracyclines in livestock due to potential downstream impacts on the environment and human health. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 03/2015; 10(10). DOI:10.1016/j.celrep.2015.02.034 · 8.36 Impact Factor
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