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Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808
Address all correspondence and requests for reprints to: Anthony E. Civitarese, Skeletal Muscle Metabolism Laboratory, Human Physiology, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, Louisiana 70808. E-mail: CivitaAE{at}pbrc.edu.
Abstract
Obesity, insulin resistance, type 2 diabetes mellitus, and aging are associated with impaired skeletal muscle oxidation capacity, reduced mitochondrial content, and lower rates of oxidative phosphorylation. Several studies have reported ultrastructural abnormalities in mitochondrial morphology and reductions in mitochondrial mass in insulin-resistant individuals. From lower organisms to rodents, mitochondrial membrane structure, function, and programmed cell death are regulated in part by the balance between the opposing forces of mitochondrial fusion and fission, suggesting they may also play an important role in human physiology.
MORE THAN 300 million individuals worldwide are projected to be afflicted with type 2 diabetes mellitus (T2DM) by the year 2025 (1). Other comorbidities that cluster with diabetes include obesity, dyslipidemia, hypertension, and inflammation. Common to all these conditions is insulin resistance (2). Although the primary cause of T2DM is unknown, it is clear that insulin resistance in skeletal muscle and liver plays a primary role in its pathogenesis before the failure of pancreatic β-cells (3). In fact, insulin resistance in the skeletal muscle of those with a family history (FH+) of T2DM has been shown to be the best predictor for the later development of T2DM (4).
T2DM is as much a disease of disordered lipid metabolism as a disease of glucose metabolism (5). Our prospective studies among Pima Indians have clearly identified impaired fat oxidation and low metabolic rate as risk factors for body weight gain and insulin resistance (6). In parallel, a strong relationship exists between elevated intracellular fatty acid metabolism and insulin resistance in the skeletal muscle of FH+ individuals (7). Defects in mitochondrial oxidative capacity have also been shown to result in hepatic steatosis in humans and mice, leading to increased hepatic glucose production and hyperglycemia (8, 9, 10). In addition, in the pancreatic β-cell, tight coupling of substrate-level synthesis of mitochondrial GTP and ATP is an important event in glucose-stimulated insulin secretion (11). Recent studies into the origins of insulin resistance and T2DM, including our work, revealed a reduced number and impaired function of skeletal muscle mitochondria in diabetes and in FH+ for T2DM as well as in elderly individuals (12, 13, 14, 15). Collectively, these data suggest that early defects in the regulation of mitochondrial mass and oxidative phosphorylation may be a contributing factor to mitochondrial dysfunction in the prediabetic state and the transition to overt T2DM. This review will focus on the role of mitochondrial dysfunction the development of insulin resistance in skeletal muscle with significant discussion on the potential role of the opposing forces of mitochondrial fusion and fission in T2DM and aging.
More than a decade ago, it was shown that low mitochondrial content and impaired lipid oxidation were present in insulin resistance (16, 17). Later, this observation was extended, and it was proposed that skeletal muscle inflexibility (impaired basal fat oxidation and blunted switch to carbohydrate oxidation in response to a meal or insulin infusion) plays a major role in the etiology of insulin resistance (18). The impairment in lipid oxidation and lower oxidative metabolism is thought to lead to the accumulation of intrahepatic and intramyocellular lipids including acylcarnitines, long-chain fatty acyl coenzymes A, diacylglycerols, and ceramides. These toxic lipids can activate serine kinases, thus inhibiting insulin signaling at the insulin receptor substrate-1 and therefore impairing glucose transport (19, 20, 21).
Mitochondrial Biogenesis and Insulin Resistance
Most research into the regulation of mitochondrial number and function has focused on nuclear transcription factors such as nuclear respiratory factors (NRF) 1 and 2 and mitochondrial transcription factor A (TFAM). Peroxisomal proliferator activator receptor 
coactivator 1
(PGC1) lies upstream of NRF1 and TFAM and serves as a nutrient-sensing system that increases mitochondrial biogenesis and shifts substrate utilization toward fat and away from carbohydrate (22). This family of nuclear receptor coactivators coordinates the transcription of both nuclear and mitochondrial genes involved in mitochondrial biogenesis (23, 24), fiber-type determination (25), lipid oxidation (12), and reactive oxygen species scavenging (12, 26). Defects in PGC1 content and signaling are found early in the development of insulin resistance. Recent studies using candidate gene analysis reported a decrease in PGC1 mRNA and the expression of genes encoding proteins of mitochondrial oxidative phosphorylation in the skeletal muscle of FH+ subjects (13) and T2DM (27). Overexpression of PGC1 in cultured myotubes results in tighter coupling of β-oxidation to tricarboxylic acid cycle, thus lowering the concentration of lipid intermediates such as acylcarnitines (28). Therefore, decreased skeletal muscle PGC1 activity and the resulting impairments in skeletal muscle and mitochondrial oxidation may lead to the development of insulin resistance in humans (28).
In the 1960s, work began to emerge describing mitochondria isolated from T2DM subjects with decreased oxidative capacity (29). Several decades later, now classical studies described reduced skeletal muscle oxidation capacity in T2DM as central to the pathogenesis of insulin resistance (30, 31). Recent studies have shown that rates of basal and insulin-stimulated ATP synthesis, measured in situ by magnetic resonance spectroscopy are reduced in individuals with T2DM (32) and subjects with FH+ for T2DM before the onset of impaired glucose tolerance (33). Such observations are of relevance because they connect the metabolic inflexibility often described in T2DM (impaired fat oxidation and blunted response to insulin) to reduced mitochondrial oxidative phosphorylation. In parallel, in vivo functional studies (34, 35) have identified reduced resting rates of ATP synthesis in elderly subjects with insulin resistance, suggesting that mitochondrial dysfunction of aging may be relevant to mitochondrial dysfunction seen in T2DM. In addition, ultrastructural defects in mitochondria of T2DM patients have also been described (36). This suggests that mitochondrial turnover and assembly (mitochondrial fusion and fission; see below) (37, 38) may be as important as reduced mitochondrial content. Taken together, these data support the hypothesis that insulin resistance in human muscle arises from defects in mitochondrial content, structure, and function leading to mitochondrial-mediated diabetes.
In rodents, muscle-specific PGC1 deletions impairs glucose tolerance; however, these mice display normal peripheral insulin sensitivity (39). Global PGC1-null mice have multiple systemic abnormalities, including complete resistance to diet-induced obesity and hyperactivity, secondary to central nervous system abnormalities (40, 41). Collectively, these studies support the hypothesis that PGC1-independent mechanisms may govern the pathogenesis of mitochondrial dysfunction in insulin-resistant states. Supportive of this notion, Morino et al. (42) did not observe decreased content of PGC-1, PGC-1β, NRF-1, NRF-2, and TFAM proteins despite a 60% increase in intramyocellular lipid content and 38% reduction in mitochondrial density in individuals with a FH+ for T2DM. The reason for the discrepancy with most human studies (12, 13, 27) may relate to 1) the measured molecular targets (mRNA vs. protein), 2) the age-dependent decrease in muscle gene expression of PGC1, 3) the ethnicity of the studied populations, 4) environmental triggers (i.e. diet), or 5) PGC1-independent mechanisms such as the balance between mitochondrial fusion and fission.
Mitochondrial Fusion and Fission, the Cellular Yin-Yang
Mitochondria carry out a vast array of cellular functions including ATP production by oxidative phosphorylation and biosynthesis of amino acids and lipids. Importantly, mitochondria are pivotal for cytosolic calcium transport (43) and play a key role in amplifying apoptotic stimuli (44), an important event in regulating the balance between cellular necrosis and/or programmed cell death. The mitochondrial contribution to cellular homeostasis and thermoregulation is indispensable to the survival of cells. In short, because of their metabolic diversity, mitochondria can be considered as the gatekeeper of cells.
Part of the functional diversity displayed by mitochondria can be attributed to the dynamic and morphological variation within mitochondrial ultrastructure and distribution. Mitochondria are active structures that collide, divide, and fuse with other mitochondria (45). Subsequently, in most mammalian cells, mitochondria exist as branched-chain reticulum networks but can also exist as punctuated structures. Their distribution within the cells is quite diverse and is mediated by the interaction with the cytoskeleton (46) and the balance between mitochondrial fusion and fission. Fusion serves to unify mitochondria and enables mixing of compartments to function in cell development, energy dissipation, and mitochondrial DNA inheritance and complementation of the mitochondrial genome (46, 47). Conversely, the opposing force of fission represents mitochondrial division and is required to promote transmission of mitochondria to dividing cells. Mitochondrial biogenesis and division occur in cells undergoing differentiation and growth in response to ATP requirements and the replacement of damaged or aging organelles (43) (Fig. 1
).
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Mitochondrial Fission
Fission in mammals is mainly controlled by two proteins: dynamin-related protein 1 (Drp1) and fission protein 1 (Fis1). Drp1 is a cytosolic GTPase protein, whereas Fis1 is localized to the outer mitochondrial membrane via a C-terminal domain and is thought to recruit Drp1 to participate in fission (52). In vitro, the overexpression of Drp1 has no phenotype, whereas knockdown of Drp1 blocks fission and results in interconnected mitochondrial tubules (53). On the other hand, perturbations in Fis1 protein content results in opposing phenotypes. For example, overexpression of Fis1 accelerates fission and causes mitochondrial fragmentation (52). Conversely, reduction in Fis1 protein inhibits fission and induces elongation of mitochondrial tubule networks (52). Ultimately, active and viable fission machinery is required to promote transmission of the mitochondrial genome during mitochondrial replication and also participates in the distribution of the organelle throughout the cell.
Mitochondrial Fusion
Mitochondrial fusion events are highly regulated, because fusion involves the recruitment of proteins localized to both the outer and inner mitochondrial membranes that act as adaptor proteins to bind mitochondrial membranes and ensure integrity of mitochondrial compartments. In lower organisms, mitochondrial fusion is regulated in part by three evolutionarily conserved GTPase proteins that form a functional complex consisting of the fuzzy onions (fzo1), mgm1, and ugo1 (54). The human homologs of fzo1 and mgm1 are mitofusin (MFN) 1 and 2 (two isoforms; MFN1/2) and optic atrophia 1 (OPA1), respectively. Mice that are deficient in either Mfn1 or -2 are embryonically lethal (55). Importantly, reductions in MFN2 protein have been shown to lower cellular respiration and glucose oxidation in mammalian fibroblasts (50). In addition, reductions in MFN2 protein are observed in obesity both in obese Zucker rats and in obese humans (50), suggesting that reduction in MFN2 expression may partially explain some of the metabolic perturbations associated with obesity.
Given the accumulating data over the past decade demonstrating impairments in oxidative phosphorylation and decreased mitochondrial mass in insulin-resistant states, it appears logical to assume that an imbalance in mitochondrial fusion and fission in metabolically active tissue such as skeletal muscle can result in defects associated with lipid and glucose metabolism such as that observed in insulin resistance and sarcopenia in aging.
Other than its role in fusion, OPA1 has several other functions, most notably the remodeling of the inner mitochondrial cristae (44) by keeping cristae junctions tight to inhibit cytochrome c release and subsequent apoptosis (38). In budding yeast (56) and in mice (38), mgm1/OPA1 is partially cleaved and processed by pcp1, an intramembrane rhomboid protease. In humans, a mutation in the OPA1 gene (-del TTAG deletion on exon 27) is associated with reduced rates of oxidative phosphorylation and ATP synthesis in skeletal muscle (57). This suggests that changes is OPA1 function resulting from either OPA1 mutations or processing by pcp1 may be associated with mitochondrial dysfunction observed in insulin-resistant states.
Is PARL Involved in the Development of Insulin Resistance and Mitochondrial Dysfunction in Skeletal Muscle?
We have previously shown that presenillin-associated rhomboid-like (PARL) protein, the human homolog of pcp1, is associated with insulin resistance and T2DM (37). PARL mRNA is reduced in the skeletal muscle of obese-diabetic Psammomys obesus (sand rat) and is positively correlated with insulin sensitivity in humans (37). In addition, PARL mRNA is lower in Pima Indians with a family history of T2DM (unpublished data). A Leu262Val polymorphism in the PARL gene is associated with increased plasma insulin, accounting for up to 5% of the variation in fasting plasma insulin in elderly (37). This interaction between the Leu262Val genotype, plasma insulin, and age is consistent with the hypothesis that defects in mitochondria increase throughout life, resulting in a decline in mitochondrial function and insulin resistance. Yeast strains without pcp1 exhibit decreased oxidative capacity, impaired growth, and fragmented mitochondria (45, 56). The insertion of the human PARL gene into pcp1-deficient yeast rescued growth and restored mitochondrial morphology in yeast, suggesting that PARL may play a similar role in human physiology (56).
Conclusion
Insulin resistance is associated with lower mitochondrial mass and function. New emerging evidence and concepts suggest that the balance between mitochondrial fusion and fission may be important in the regulation of mammalian mitochondrial energetics. Two studies have described reductions in the proteins involved in mitochondrial fusion (MFN2 and PARL) in insulin-resistant states. There is growing evidence that a reduction in mitochondrial fusion is an important etiological factor in the development of obesity, insulin resistance, T2DM, and age-associated diseases. Such impaired fusion results in lower mitochondrial content and therefore impaired oxidative capacity, leading to a defective energy homeostasis.
Acknowledgments
We thank Dr. Darcy Johansen for her review and critical comments on the manuscript.
Footnotes
First Published Online January 17, 2008
Abbreviations: Drp1, Dynamin-related protein 1; FH+, family history; Fis1, fission protein 1; MFN, mitofusin; NRF, nuclear respiratory factor; OPA1, optic atrophia 1; PARL, presenillin-associated rhomboid-like; PGC1, peroxisomal proliferator activator receptor coactivator 1; T2DM, type 2 diabetes mellitus; TFAM, mitochondrial transcription factor A.
This review was supported partly by RO1 AG20478 (E.R.) and CNRU P30 DK072476 (E.R.).
Disclosure Summary: The authors have nothing to disclose.
Received October 22, 2007.
Accepted for publication January 7, 2008.
References
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  F. Distelmaier, W. J.H. Koopman, L. P. van den Heuvel, R. J. Rodenburg, E. Mayatepek, P. H.G.M. Willems, and J. A.M. Smeitink Mitochondrial complex I deficiency: from organelle dysfunction to clinical disease Brain, April 1, 2009; 132(4): 833 - 842. [Abstract] [Full Text] [PDF]
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