Despite this paradigm being attractive, a potential caveat applies to this model. Indeed, skeletal muscle is characterised by an enormous spare respiratory capacity allowing for a 10—fold increase in oxygen consumption above resting, which denies the possibility that a decrease in mitochondrial function of the magnitude observed in type 2 diabetic individuals might lead to the accumulation of diacylglycerol and ceramide Holloszy, Nonetheless, skeletal muscle can call upon its spare respiratory capacity in situations of increased energy demand i.
Thus, in the absence of stimuli that trigger mitochondrial adaptation to match increased energy demand, as in response to AMPK activation, even slight changes in mitochondria oxidative capacity, if protracted over time, will result in ectopic lipid accumulation Figure 2 ; Montgomery and Turner, Mitochondrial dysfunction and insulin resistance.
Impaired mitochondria oxidative capacity leads to a decrease in metabolic substrate catabolism resulting in increased intramyocellular fatty acids availability, which may be channelled towards lipotoxic lipid species biosynthesis i.
Increased nutrient supplies also induce an increase in mitochondrial reactive oxygen species ROS production, which can directly induce insulin resistance and elicit oxidative damage to mitochondrial DNA, protein and lipid promoting the removal of damaged mitochondria by mitophagy. Another putative mechanism linking mitochondrial dysfunction to insulin resistance is represented by the generation of reactive oxygen species ROSs by mitochondria.
ROSs are mandatory by-products of mitochondrial energy metabolism with their production being counterbalanced by the intracellular antioxidant system. However, when ROS production overwhelms cellular antioxidant capacity, oxidative stress occurs Schieber and Chandel, An increase in electron donors derived from nutrient oversupply and catabolism increases electron supply to the mitochondrial electron transport chain, which in turn induces a high proton gradient across the inner mitochondrial membrane, which, if not coupled to an increase in ATP synthesis, culminates in greater ROS production.
The increase in ROS generation and the parallel oxidative stress are not without consequence for mitochondria oxidative metabolism. Indeed, ROS can directly induce oxidative damage to mitochondrial DNA, protein and lipids and consequently trigger the removal of damaged mitochondria by mitophagy Figure 2. The consequent decrease in mitochondrial function and density compromises overall cellular oxidative capacity, thereby favouring the ectopic accumulation of lipotoxic lipid intermediates.
Despite the well-documented association between mitochondrial dysfunction and insulin resistance, whether impaired mitochondrial oxidative capacity is causal to or is a consequence of insulin resistance remains a matter of debate with several authors failing to confirm this association.
However, whether this mechanism holds true in skeletal muscle remains to be elucidated. Animal studies aimed at shedding the light on the role of mitochondrial function in the pathogenesis of insulin resistance also failed to confirm a direct cause-effect relationship between insulin resistance and defective mitochondrial oxidative metabolism.
Similar to humans, diet-induced insulin resistance in rats and mice was not associated with a decrease in skeletal muscle mitochondrial proteins. According to the evidence described so far, the relationship between insulin resistance and mitochondrial dysfunction can be exemplified by three different scenarios: impaired mitochondrial function is associated with insulin resistance, insulin resistance develops despite mitochondrial function remaining unaffected and finally mitochondria oxidative capacity is increased despite the development of diet-induced insulin resistance.
Thus, mitochondrial dysfunction does not appear to be a prerequisite for the onset of insulin resistance. A possible explanation to this conundrum is the compensatory increase in mitochondrial function to offset fatty acid oversupply and prevent their deleterious effects of insulin signalling.
While this protective mechanism may prevent researchers from detecting slight, but significant defects in mitochondria biology, the time course and the magnitude of this adaptation may not suffice to counteract the increase in fatty acid availability and prevent ectopic lipid accumulation Montgomery and Turner, Thus, independently of whether mitochondrial dysfunction is a cause or a consequence of insulin resistance, boosting mitochondrial function remains a promising strategy to improve insulin sensitivity.
Nonetheless, the majority of genes involved in mitochondrial metabolism and biogenesis are nuclear-encoded genes whose transcription, translation and transport into the mitochondria occur in concomitance and are coordinated with mtDNA replication, transcription and translation.
Regulation of mitochondrial biogenesis, fusion and supercomplex formation. Mitochondrial function is also modulated by shifts in mitochondria dynamics with a drop in ATP levels or an increase in ATP demand triggering mitochondria fusion also depicted in the fluorescent microscopy picture of myotube mitochondria stained with Mitotracker red Thermo Fisher Scientific cells were purchased from Cook Myosite, USA.
Finally, mitochondrial complexes can assemble into multimeric super assembled structures termed supercomplexes. Exercise has been shown to promote supercomplex formation, which, instead, was reported to be decreased in individuals affected by type 2 diabetes T2DM. Indeed, AMPK inhibits gluconeogenesis, de novo fatty acid and protein synthesis as well as cell growth.
It inhibits fatty acid and sterol synthesis by phosphorylating acetyl-CoA carboxylase, which catalyses the first step in the de novo lipid synthesis and hydroxymethylglutaryl-CoA reductase the rate-limiting step in cholesterol synthesis, whereas the phosphorylation of glycogen synthases 1 and 2 underpins AMPK-mediated inhibition of glycogen synthesis Herzig and Shaw, Protein Acetylation as a Regulator of Mitochondrial Function The regulation of mitochondria biogenesis and the expression of genes orchestrating oxidative metabolism are not the only determinant of mitochondrial function.
Indeed, mitochondrial activity and oxidative capacity are also regulated by post-transcriptional modifications of the mitochondria electron transport chain complexes and mitochondrial enzymes involved in oxidative metabolism. Thus, mitochondrial protein acetylation is susceptible to changes in energy or nutrient availability independently on whether such metabolic perturbation arises from nutrient deficiency or excess.
However, despite an increase in protein acetylation in both the fed and fasted state, these metabolic states promote different acetylation patterns. Particularly, hyperacetylated mitochondrial proteins have reduced activity resulting in mitochondrial dysfunction and lower ATP production Anderson and Hirschey, A pivotal regulator of mitochondrial protein acetylation, and thereby energy metabolism, is the mitochondrial NAD-dependent protein deacetylase SIRT3.
Mitochondrial Dynamics Mitochondrial function is further regulated by acute changes in mitochondrial architecture, termed mitochondria dynamics, which encompasses cycles of fusion and fission and is crucial to allow the cells to respond to short-term metabolic perturbations Wai and Langer, Despite mitochondria being classically portrayed as single isolated organelles, they are highly dynamic and capable of engaging in intimate interactions with other cellular components and dividing fission or fuse joining fusion depending on the metabolic status of the cell McInnes, The maintenance of a healthy cellular mitochondrial network is dependent on the balance between fusion and fission cycles Westermann, , which in turn are governed by cellular metabolic perturbations and metabolic demand Wai and Langer, and respond to fluctuation in the energy status of the cell Liesa and Shirihai, depending on the cell type.
On the contrary, an excess in substrates that fuel oxidative metabolism induces a shift towards mitochondria fission, which is associated with an increase in ROS production, impaired oxidative phosphorylation and depletion of mtDNA Liesa and Shirihai, It appears that it is not the pace at which the ETC works that determines ROS production rate, but rather the redox state of the ubiquinone pool.
Therefore, the quality of the ubiquinone pool may be more important than the rate of metabolism in determining longevity. In this issue of Genes and Development, Hekimi and colleagues Liu et al. Previous Section Next Section Mutations and perturbations that alter mitochondrial function and life span Mitochondria are the primary sites of oxygen free-radical production.
Consistent with this prediction, yeast, worms, flies, or mice that overexpress antioxidant defenses live longer Melov et al. Although these studies showed that protection against ROS results in increased life span, the use of genetic approaches to alter mitochondria to study the aging process is not straight-forward since, a priori, this organelle is indispensable for life.
However, research in nematodes identified the mitochondrial oxidative phosphorylations as regulators of the aging process. Three studies demonstrated that reduction of function of several mitochondrial genes extends the life span of fully developed, adult worms.
Siegfried Hekimi's lab showed that a single mutation in an iron sulfur component of complex III, isp-1, increased longevity Feng et al. This mutation decreases oxygen consumption, suggesting that it lowers the activity of the electron transport chain Feng et al. Two independent RNA interference RNAi -based screens, in the Ruvkun and Kenyon laboratories, also showed that components of the mitochondrial electron transport chain increased longevity when they were inactivated using RNAi Dillin et al.
This knockdown also resulted in reduced ATP levels, O2 consumption, and slowed the rate of development and other physiological processes, including eating, movement, and defecation Dillin et al.
Mutations in another worm gene, clk-1, is discussed in greater detail below. Not all mitochondrial ETC lesions increase longevity. The mev-1 kn1 mutation is probably the best example of a mutation that decreases mitochondrial activity, but does not increase longevity. The mev-1 kn1 mutation was identified in a genetic screen to identify mutations that resulted in worms that were more sensitive to the drug methyl viologen paraquat. Cells treated with paraquat produce excess oxygen free radicals.
Additionally, mev-1 kn1 mutant animals have higher levels of oxygen free radicals compared to wild-type animals Senoo-Matsuda et al. Similar to mev-1 kn1 mutant animals, gas-1 fc21 mutant animals are also hypersensitive to paraquat, short lived, have reduced ETC activity, and have higher levels of oxygen free radicals compared to wild-type animals Senoo-Matsuda et al. Besides mev-1 and gas-1 mutations, nuo-1 ua1 and atp-2 ua2 mutant worms also have deficient mitochondrial respiratory chains Tsang et al.
Taken together, a clear correlation between mitochondrial metabolic activity and longevity cannot be derived from these studies. For example, clk-1 mutant animals are long-lived, but have normal respiratory rates, and RNAi of several ETC components results in increased longevity and decreased metabolic rates.
Therefore, defining the role that mitochondria play in the aging process will be essential to elucidating the link between metabolic rates and longevity. Previous Section Next Section clk-1 In this issue of Genes and Development, it is reported that a loss-of-function mutation in the gene mclk1 leads to a life-span extension in mice Liu et al.
As explained above, these molecules are central to both mitochondrial respiration and superoxide production. Over the past decade, the mechanism by which the ubiquinone synthesis pathway influences longevity has been the focus of much investigation. Although a great deal of headway has been made, the mechanism by which clk-1 imparts its beneficial effects is unknown.
The protracted embryonic cell cycle and larval development eventually result in fertile adults that continue to display slowed biological functions.
These animals show a reduction in egg laying rate as well as a decreased number of eggs produced. Defecation rates were slowed by 1. Most notably, the mean and maximum life span were increased in the three clk-1 mutants. From these results, it appears that clk-1 may act early during the animal's life cycle to help set the rate of living of the entire organism for the remainder of its life.
The various phenotypes, especially the life-span extension, inspired further investigation of clk-1 to determine the function and the degree of conservation between species. The worm clk-1 gene was mapped to chromosome III, and the residue protein was determined to be highly similar in structure and function to the Saccharomyces cerevisiae Coq7p protein and conserved among eukaryotes, including humans Ewbank et al. Yeast coq7p is an enzyme 3-methoxymethylpolyprenyl-benzoquinone-hydroxylase required for the penultimate step in ubiquinone Q biosynthesis.
Cells lacking coq7p cannot produce ubiquinone and accumulate dimethoxy-ubiquinone DMQ Stenmark et al. Because of the respiration defects of yeast lacking coq7p, it was difficult to reconcile that clk-1 mutant worms are able to perform mitochondrial respiration at near normal levels. Jonassen et al. When they grew worms on Escherichia coli strains unable to produce ubiquinone, the clk-1 mutant worms arrested at the L2 larval stage of development and failed to develop into reproductive adults Jonassen et al.
The shorter the isoprenyl chain, the more severe the phenotype Hihi et al. Whether mitochondrial respiration is affected is unclear, since Levavasseur et al. More direct experiments are still needed to clarify this issue. This is similar to the phenotypes observed in the worm, suggesting a conserved function from nematodes to mammals. This is consistent with the fact that the apoptotic pathway is known to be dependent on ROS concentration ChanC HPLC traces of quinone extracts recorded at nm. Our data provide evidence for decreased mitochondrial CoQ content and resultant generation of oxidants being a convergent pathway for many different models of insulin resistance. Further experiments suggested a link between the lower levels of CoQ and the higher levels of oxidants in the mitochondria. Mitochondrial Dysfunction and Insulin Resistance A decrease in metabolic substrate oxidation appears as a primary defect, which, by triggering a cascade of events culminating with the intracellular accumulation of the diacylglycerol and ceramide, hampers insulin signalling and promotes insulin resistance. These animals show a reduction in egg laying rate as well as a decreased number of eggs produced. Addition of the Complex IV inhibitor cyanide to cell suspension resulted in a complete inhibition of oxygen consumption, confirming that the detected oxygen consumption was predominantly of mitochondrial origin. This article reviews the relationships among different stress, mitochondrial dysfunction, and T2DM and examines the insulin for potential use of Essays using ethos pathos logos Q10 as a supplement for the biosynthesis of T2DM. A OCR of intact fellows measured polarographically. Open in new tab Showing slide Oxygen consumption and grandparents of mitochondrial respiratory enzymes. This life-span extension requires activity of the forkhead-family cruise factor DAF However, in fiddler to DMQ9, other ways species dietary UQ8 and endogenous rhodoquinone have been magical to be present in clk-1worms 5354 and they could be insulin for at biosynthesis some of the mitochondrial deed transport in those mutants. Thus, mitochondrial insulin acetylation is susceptible to changes in doing or nutrient availability plenty on whether such metabolic perturbation arises from reputable deficiency or excess. Wherefore, reduced UQ is an important antioxidant in need membranes and lipoproteins 3. Still, it remains to be clearly defined whether the liver is the only child where LOH occurs and, if so, if this dissertation is responsible for the only longevity that is observed. However, this biosynthesis is slowly being overturned.
Insulin upon binding to its receptor activates a signal transduction pathway culminating in the PDK1 and mTORC2-mediated phosphorylation and activation of AKT, which, by modulating its downstream effectors, promotes glucose uptake, glycolysis and glycogen synthesis in skeletal muscle. This intuitive association between impaired mitochondrial oxidative capacity and insulin resistance has been confirmed in landmark studies, which described an impairment in mitochondrial function in individuals diagnosed with T2DM. Further research is therefore needed to investigate whether CoQ might provide the link between statins and type 2 diabetes. Mitochondrial Dysfunction and Insulin Resistance A decrease in metabolic substrate oxidation appears as a primary defect, which, by triggering a cascade of events culminating with the intracellular accumulation of the diacylglycerol and ceramide, hampers insulin signalling and promotes insulin resistance. It is a key component in the electron transport chain in the mitochondria. Thus, in the absence of stimuli that trigger mitochondrial adaptation to match increased energy demand, as in response to AMPK activation, even slight changes in mitochondria oxidative capacity, if protracted over time, will result in ectopic lipid accumulation Figure 2 ; Montgomery and Turner,
Second, there are highly robust in vitro adipocyte models 3T3-L1 cells that accurately recapitulate both insulin action and the generation of insulin resistance using a range of insults that mimic perturbations implicated in insulin resistance in vivo such as hyperinsulinemia, inflammation and glucocorticoids. Superoxide and hydroxyl radicals are examples of ROS. Second, pyruvate is transferred into the mitochondria and broken down by the tricarboxylic acid cycle. Of note, obesity and visceral fat accumulation in particular are underlain by a low-grade chronic inflammation Hotamisligil, and increased ectopic fat storage in metabolically active tissues including skeletal muscle and liver, a phenomenon termed lipotoxicity Unger, Previous Section Next Section Future thoughts The paper published in this issue of Genes and Development makes significant observations that point to a mechanism that seems to be conserved from worms to mice in the regulation of life span Liu et al.
E Scatter plot of z-scores for pathways from proteomic analysis of insulin-resistant tissue y-axis or cells x-axis. Human figures represent expression of pathways or proteins in human data Supplementary file 3.