Mitochondrial Dynamics in the Regulation of Nutrient Utilization and Energy Expenditure

ArticleinCell metabolism 17(4):491-506 · April 2013with32 Reads
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.
    • "Also relevant for the debate is the notion that the many functions of mitochondria are dictated by their dynamic morphology. Indeed, the role of mitochondrial dynamics in nutrient metabolism and the metabolic syndrome is becoming increasingly clear [212]. With respect to mitochondrial models of insulin resistance (Section 4), 2 key functions, oxidative phosphorylation and ROS production, warrant explicit discussion. "
    [Show abstract] [Hide abstract] ABSTRACT: Skeletal muscle insulin resistance in obesity associates with mitochondrial dysfunction, but the causality of this association is controversial. This review evaluates mitochondrial models of nutrient-induced muscle insulin resistance. It transpires that all models predict that insulin resistance arises as a result of imbalanced cellular bioenergetics. The nature and precise origin of the proposed insulin-numbing molecules differ between models but all species only accumulate when metabolic fuel supply outweighs energy demand. This observation suggests that mitochondrial deficiency in muscle insulin resistance is not merely owing to intrinsic functional defects, but could instead be an adaptation to nutrient-induced changes in energy expenditure. Such adaptive effects are likely because muscle ATP supply is fully driven by energy demand. This market-economic control of myocellular bioenergetics offers a mechanism by which insulin-signalling deficiency can cause apparent mitochondrial dysfunction, as insulin resistance lowers skeletal muscle anabolism and thus dampens ATP demand and, consequently, oxidative ATP synthesis.
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    • "All the known functions that can be ascribed to mitochondria are largely dependent on their ability to dynamically modify their shape and morphology according to cellular requirements [30]. Likewise, in a condition where the proper control of mitochondrial morphology (usually referred to as mitochondrial dynamism) is compromised, cell mis-functioning and degeneration, including neurodegeneration, take place [31]. "
    [Show abstract] [Hide abstract] ABSTRACT: Alterations in the structure and functions of mitochondria are a typical trait of Amyotrophic Lateral Sclerosis, a neurodegenerative disease characterized by a prominent degeneration of upper and lower motor neurons. The known gene mutations that are responsible for a small fraction of ALS cases point to a complex interplay between different mechanisms in the disease pathogenesis. Here we will briefly overview the genetic and mechanistic evidence that make dysfunction of mitochondria a candidate major player in this process.
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    • "Fission of mitochondria is controlled by Fis1, Drp1, and Mff proteins. A correct balance between fusion and fission is essential for mitochondrial function and cellular homeostasis (Liesa & Shirihai, 2013). Besides its role in mitochondrial fusion, Mfn2 has been described to be involved in the regulation of cell proliferation, oxidative metabolism , autophagy, mitophagy, mitochondrial antiviral signaling, and unfolded protein response (Bach et al, 2003; Chen et al, 2004; Yasukawa et al, 2009; Hailey et al, 2010; Ngoh et al, 2012; Zhao et al, 2012; Chen & Dorn, 2013; Munoz et al, 2013). "
    [Show abstract] [Hide abstract] ABSTRACT: Mitochondrial dysfunction and accumulation of damaged mitochondria are considered major contributors to aging. However, the molecular mechanisms responsible for these mitochondrial alterations remain unknown. Here, we demonstrate that mitofusin 2 (Mfn2) plays a key role in the control of muscle mitochondrial damage. We show that aging is characterized by a progressive reduction in Mfn2 in mouse skeletal muscle and that skeletal muscle Mfn2 ablation in mice generates a gene signature linked to aging. Furthermore, analysis of muscle Mfn2-deficient mice revealed that aging-induced Mfn2 decrease underlies the age-related alterations in metabolic homeostasis and sarcopenia. Mfn2 deficiency reduced autophagy and impaired mitochondrial quality, which contributed to an exacerbated age-related mitochondrial dysfunction. Interestingly, aging-induced Mfn2 deficiency triggers a ROS-dependent adaptive signaling pathway through induction of HIF1α transcription factor and BNIP3. This pathway compensates for the loss of mitochondrial autophagy and minimizes mitochondrial damage. Our findings reveal that Mfn2 repression in muscle during aging is a determinant for the inhibition of mitophagy and accumulation of damaged mitochondria and triggers the induction of a mitochondrial quality control pathway.
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