Mitochondrial stress: A bridge between mitochondrial dysfunction and metabolic diseases?

Hu, Fang; Liu, Feng

doi:10.1016/j.cellsig.2011.05.008

Cited by 97 publications

(82 citation statements)

References 95 publications

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“…Mitochondrial stress and impaired gut wall integrity are candidate underlying processes that may be improved by bar consumption. Both of these conditions are common in the obese (84,85), and both are linked to poor diets (86,87) and to insulin resistance and inflammation (88,89). Bar-induced reduction of mitochondrial stress and improved gut integrity would be expected to have multiple beneficial consequences similar to the metabolic improvements observed in this study.…”

Section: Possible Mechanismsmentioning

confidence: 60%

A multicomponent nutrient bar promotes weight loss and improves dyslipidemia and insulin resistance in the overweight/obese: chronic inflammation blunts these improvements

McCann¹,

Shigenaga²,

Mietus‐Snyder³

et al. 2015

The FASEB Journal

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This study determined if twice-daily consumption of a nutrient-dense bar intended to fill gaps in Western diets, without other dietary/lifestyle requirements, favorably shifted metabolic/anthropometric indicators of dysregulation in a healthy direction. Three 8-wk clinical trials in 43 healthy lean and overweight/obese (OW/OB) adults, who served as their own controls, were pooled for analysis. In less inflamed OW/OB [highsensitivity C-reactive protein (hsCRP) <1.5], statistically significant decreases occurred in weight (21.1 6 0.5 kg), waist circumference (23.1 6 1.4 cm), diastolic blood pressure (24.1 6 1.6 mmHg), heart rate [HR; 24.0 6 1.7 beats per minute (bpm)], triglycerides (272 6 38.2 mg/dl), insulin resistance (homeostatic model of insulin resistance) (20.72 6 0.3), and insulin (22.8 6 1.3 mU/L); an increase in HDL-2b (+303 6 116 nM) and realignment of LDL lipid subfractions toward a less atherogenic profile [decreased small LDL IIIb (244 6 23.5 nM), LDL IIIa (299 6 43.7 nM), and increased large LDL I (+66 6 28.0 nM)]. In the more inflamed OW/OB (hsCRP >1.5), inflammation was reduced at 2 wk (20.66 mg/L), and HR at 8 wk (23.4 6 1.3 bpm). The large HDL subfraction (10.5-14.5 nm) increased at 8 wk (+346 6 126 nM). Metabolic improvements were also observed in lean participants. Thus, favorable changes in measures of cardiovascular health, insulin resistance, inflammation, and obesity were initiated within 8 wk in the OW/OB by replacing deficiencies in Western diets without requiring other dietary or lifestyle modifications; chronic inflammation blunted most improvements. , fiber, and plant polyphenolics (1-4), is a major cause of the increasing prevalence of obesity worldwide (5-7). Such diets directly contribute to the metabolic dysregulation that usually accompanies obesity (8)(9)(10)(11) and is also present in ;25% of lean individuals (12, 13). Metabolic dysregulation includes chronic inflammation, insulin resistance, dyslipidemia, and oxidative stress (14, 15). Several metabolic abnormalities, together with visceral adiposity and high blood pressure (BP), are collectively termed "the metabolic syndrome" (11, 16). Various aspects of metabolic dysregulation have been shown to be independent risk factors for cardiovascular disease (CVD) and type 2 diabetes, and putative risk factors for the many other obesityassociated diseases including cancer, autoimmune disorders, asthma, and neurodegenerative conditions (17)(18)(19)(20)(21)(22).Because poor diets are a root cause of these health problems, an obvious approach to the obesity epidemic would be to improve dietary habits. However, changing dietary patterns is difficult for many people to initiate and sustain (23-25).Abbreviations: aka, also known as; BMI, body mass index; BP, blood pressure; bpm, beats per minute; CVD, cardiovascular disease; DBP, diastolic blood pressure; DHA, docosahexaenoic acid; HDL-L, large HDL subfraction; HDLPs, total HDL subfractions; HOMA-IR, homeostatic model of insulin resistance; HPMC, hydroxypropylmethylcellulose; HR, ...

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Section: Possible Mechanismsmentioning

confidence: 60%

A multicomponent nutrient bar promotes weight loss and improves dyslipidemia and insulin resistance in the overweight/obese: chronic inflammation blunts these improvements

McCann¹,

Shigenaga²,

Mietus‐Snyder³

et al. 2015

The FASEB Journal

View full text Add to dashboard Cite

show abstract

“…Several mechanisms have been proposed to be responsible for obesity-related insulin resistance, including lipid accumulation in non-adipose tissues, inflammation, mitochondrial dysfunction, and/or oxidative stress [14][15][16][17][18]. Much of the evidence supporting these various theories is based on studies in normal or genetically manipulated mice fed HFDs.…”

Section: Introductionmentioning

confidence: 99%

Mouse strain-dependent variation in obesity and glucose homeostasis in response to high-fat feeding

et al. 2013

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Aims/hypothesis Metabolic disorders are commonly investigated using knockout and transgenic mouse models. A variety of mouse strains have been used for this purpose. However, mouse strains can differ in their inherent propensities to develop metabolic disease, which may affect the experimental outcomes of metabolic studies. We have investigated straindependent differences in the susceptibility to diet-induced obesity and insulin resistance in five commonly used inbred mouse strains (C57BL/6J, 129X1/SvJ, BALB/c, DBA/2 and FVB/N). Methods Mice were fed either a low-fat or a high-fat diet (HFD) for 8 weeks. Whole-body energy expenditure and body composition were then determined. Tissues were used to measure markers of mitochondrial metabolism, inflammation, oxidative stress and lipid accumulation. Results BL6, 129X1, DBA/2 and FVB/N mice were all susceptible to varying degrees to HFD-induced obesity, glucose intolerance and insulin resistance, but BALB/c mice exhibited some protection from these detrimental effects. This protection could not be explained by differences in mitochondrial metabolism or oxidative stress in liver or muscle, or inflammation in adipose tissue. Interestingly, in contrast with the other strains, BALB/c mice did not accumulate excess lipid (triacylglycerols and diacylglycerols) in the liver; this is potentially related to lower fatty acid uptake rather than differences in lipogenesis or lipid oxidation. Conclusions/interpretation Collectively, our findings indicate that most mouse strains develop metabolic defects on an HFD. However, there are inherent differences between strains, and thus the genetic background needs to be considered carefully in metabolic studies. Keywords

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“…In mammalian cells, the UPR mt has been addressed mainly by altering protein function or by the generation of high amounts of misfolded proteins [3,14,56]. Numerous approaches altered ClpP protein levels or activity [9,59,60] [14,56,61] or in the context of metabolic disease [62]. These analyses likely blend several activated cellular signaling pathways, and it has been rather difficult to distinguish between the UPR mt regulators and effectors.…”

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confidence: 99%

ClpX stimulates the mitochondrial unfolded protein response (UPRmt) in mammalian cells

Al-Furoukh

Ianni

Nolte

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Proteostasis is crucial for life and maintained by cellular chaperones and proteases. One major mitochondrial protease is the ClpXP complex, which is comprised of a catalytic ClpX subunit and a proteolytic ClpP subunit. Based on two separate observations, we hypothesized that ClpX may play a leading role in the cellular function of ClpXP. Therefore, we analyzed the effect of ClpX overexpression on a myoblast proteome by quantitative proteomics. ClpX overexpression results in the upregulation of markers of the mitochondrial proteostasis pathway, known as the "mitochondrial unfolded protein response" (UPRmt). Although this pathway is described in detail in Caenorhabditis elegans, it is not clear whether it is conserved in mammals. Therefore, we compared features of the classical nematode UPRmt with our mammalian ClpX-triggered UPRmt dataset. We show that they share the same retrograde mitochondria-to-nucleus signaling pathway that involves the key UPRmt transcription factor CHOP (also known as Ddit3, CEBPZ or GADD153). In conclusion, our data confirm the existence of a mammalian UPRmt that has great similarity to the C. elegans pathway. Furthermore, our results illustrate that ClpX overexpression is a good and simple model to study the underlying mechanisms of the UPRmt in mammalian cells.

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Mitochondrial stress: A bridge between mitochondrial dysfunction and metabolic diseases?

Cited by 97 publications

References 95 publications

A multicomponent nutrient bar promotes weight loss and improves dyslipidemia and insulin resistance in the overweight/obese: chronic inflammation blunts these improvements

A multicomponent nutrient bar promotes weight loss and improves dyslipidemia and insulin resistance in the overweight/obese: chronic inflammation blunts these improvements

Mouse strain-dependent variation in obesity and glucose homeostasis in response to high-fat feeding

ClpX stimulates the mitochondrial unfolded protein response (UPRmt) in mammalian cells

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