Mitochondrial response to nutrient availability and its role in metabolic disease - PubMed (original) (raw)

Review

Mitochondrial response to nutrient availability and its role in metabolic disease

Arwen W Gao et al. EMBO Mol Med. 2014 May.

Abstract

Metabolic inflexibility is defined as an impaired capacity to switch between different energy substrates and is a hallmark of insulin resistance and type 2 diabetes mellitus (T2DM). Hence, understanding the mechanisms underlying proper metabolic flexibility is key to prevent the development of metabolic disease and physiological deterioration. An important downstream player in the effects of metabolic flexibility is the mitochondrion. The objective of this review was to describe how mitochondrial metabolism adapts to limited nutrient situations or caloric excess by changes in mitochondrial function or biogenesis, as well as to define the mechanisms propelling these changes. Altogether, this should pinpoint key regulatory points by which metabolic flexibility might be ameliorated in situations of metabolic disease.

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Figures

Figure 1

Figure 1

Mitochondrial dynamics and quality control. Mitochondrial dynamics involves repetitive cycles of mitochondrial fusion and fission. Fusion of mitochondria is regulated by mitofusin (Mfn) 1 and Mfn2 (both proteins are required for mitochondrial outer membrane fusion) and optic atrophy 1 (Opa1) (required for mitochondrial inner membrane fusion protein). Mitochondrial fission is regulated by dynamin-related protein 1 (Drp1), mitochondrial fission factor (Mff), and fission 1 (Fis1). When a daughter mitochondrion is dysfunctional/depolarized, it will be targeted for elimination. The defective mitochondria accumulate tensin homolog-induced putative kinase protein 1 (PINK1) at the mitochondrial surface, which in turn recruits Parkin. Parkin-induced ubiquitylation of the outer membrane initiates the recruitment of autophagosomes, which are degraded after fusion with a lysosome.

Figure 2

Figure 2

The acute (A) and transcriptional (B) regulation of mitochondrial networks upon caloric restriction and fasting. (A) When nutrients are limited, cAMP levels rise and activate protein kinase A (PKA). PKA in turn phosphorylates and inactivates Drp1, thereby blocking mitochondrial fission. This relative switch to elongated mitochondria increases ATP levels as a response to nutrients scarcity. Nutrient scarcity also increases the level of mitochondrial NAD+, leading to the activation of SIRT3 and improving mitochondrial function through deacetylation of ket SIRT3 targets (e.g., mitochondrial complex I protein NDUFA9, the superoxide dismutase 2 (SOD2), and fatty acid oxidation enzyme LCAD. (B) Upon caloric restriction and fasting, AMP-activated protein kinase (AMPK) is activated by an increase in the ratio of AMP relative to ATP. AMPK phosphorylates several transcriptional (co)activators, such as PCG-1α, forkhead box O (FOXO). This primes these regulators for SIRT1-dependent deacetylation, which is further enhanced by a concurrent increase in NAD+ levels.

Figure 3

Figure 3

The acute (A) and transcriptional (B, C) regulation of mitochondrial networks upon caloric excess and obesity. (A) Upon caloric excess, lipid overload triggers mitochondrial fission, which is accompanied by mitochondrial uncoupling and ATP depletion. The enhanced mitochondrial uncoupling may be a solution to consume excess energy and prevent fat deposition in the cells. At the same time, decreased NAD+ levels and reduced SIRT3 protein content lead to SIRT3 activity, mitochondrial hyperacetylation, and mitochondrial dysfunction. (B) Caloric excess inhibits AMPK activity because of high intracellular ATP levels. This reduces NAD+ levels and SIRT1 activity. As a consequence, the transcriptional regulators that are subject to SIRT1 deacetylation are attenuated. This is further emphasized by the activation of steroid receptor coactivator protein 1 (SRC3) and the acetyltransferase GCN5. (C) During high-fat diet feeding, the nuclear receptor corepressor 1 (NCoR1) is upregulated and thereby represses the activity of key transcription factors that modulate mitochondrial activity, such as nuclear respiratory factor 1 (NRF1), NRF2, and estrogen-related receptors (ERRs), as well as peroxisome proliferator-activated receptors (PPARs).

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