Transgenic Control of Mitochondrial Fission Induces Mitochondrial Uncoupling and Relieves Diabetic Oxidative Stress

Galloway, Chad A.; Lee, Hakjoo; Nejjar, S.; Jhun, Bong Sook; Yu, Tianzheng; Hsu, Wei-Hsuan; Yoon, Yisang

doi:10.2337/db11-1640

Cited by 76 publications

(95 citation statements)

References 51 publications

(43 reference statements)

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“…Electron microscopy studies have shown that the mean size of mitochondria was larger in DN compared with those in normal controls (41). Similar findings were described for mitochondria in RPTC of streptozotocin-induced diabetic mice (42). Increased IHG-1 expression, leading to increased mitochondrial fusion, may be a recovery mechanism in response to hyperglycemic stress.…”

Section: Discussionsupporting

confidence: 66%

IHG-1 Increases Mitochondrial Fusion and Bioenergetic Function

et al. 2014

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Induced in high glucose-1 (IHG-1) is a conserved mitochondrial protein associated with diabetic nephropathy (DN) that amplifies profibrotic transforming growth factor (TGF)-β1 signaling and increases mitochondrial biogenesis. Here we report that inhibition of endogenous IHG-1 expression results in reduced mitochondrial respiratory capacity, ATP production, and mitochondrial fusion. Conversely, overexpression of IHG-1 leads to increased mitochondrial fusion and also protects cells from reactive oxygen species–induced apoptosis. IHG-1 forms complexes with known mediators of mitochondrial fusion—mitofusins (Mfns) 1 and 2—and enhances the GTP-binding capacity of Mfn2, suggesting that IHG-1 acts as a guanine nucleotide exchange factor. IHG-1 must be localized to mitochondria to interact with Mfn1 and Mfn2, and this interaction is necessary for increased IHG-1–mediated mitochondrial fusion. Together, these findings indicate that IHG-1 is a novel regulator of both mitochondrial dynamics and bioenergetic function and contributes to cell survival following oxidant stress. We propose that in diabetic kidney disease increased IHG-1 expression protects cell viability and enhances the actions of TGF-β, leading to renal proximal tubule dedifferentiation, an important event in the pathogenesis of this devastating condition.

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Section: Discussionsupporting

confidence: 66%

IHG-1 Increases Mitochondrial Fusion and Bioenergetic Function

et al. 2014

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“…Previous studies have demonstrated that fragmentation of mitochondria within the kidney is linked to both acute (44) and chronic (37,45,46) renal injury and that it is likely that this is the reason for the inability of the diabetic Aifm1…”

Section: Discussionmentioning

confidence: 99%

Deficiency in Apoptosis-Inducing Factor Recapitulates Chronic Kidney Disease via Aberrant Mitochondrial Homeostasis

et al. 2016

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Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein with dual roles in redox signaling and programmed cell death. Deficiency in AIF is known to result in defective oxidative phosphorylation (OXPHOS), via loss of complex I activity and assembly in other tissues. Because the kidney relies on OXPHOS for metabolic homeostasis, we hypothesized that a decrease in AIF would result in chronic kidney disease (CKD). Here, we report that partial knockdown of Aif in mice recapitulates many features of CKD, in association with a compensatory increase in the mitochondrial ATP pool via a shift toward mitochondrial fusion, excess mitochondrial reactive oxygen species production, and Nox4 upregulation. However, despite a 50% lower AIF protein content in the kidney cortex, there was no loss of complex I activity or assembly. When diabetes was superimposed onto Aif knockdown, there were extensive changes in mitochondrial function and networking, which augmented the renal lesion. Studies in patients with diabetic nephropathy showed a decrease in AIF within the renal tubular compartment and lower AIFM1 renal cortical gene expression, which correlated with declining glomerular filtration rate. Lentiviral overexpression of Aif1m rescued glucose-induced disruption of mitochondrial respiration in human primary proximal tubule cells. These studies demonstrate that AIF deficiency is a risk factor for the development of diabetic kidney disease.

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“…Changes in mitochondrial morphology occur coordinately with metabolic flux, changing morphology in both an excess and lack of nutrients. Generally, mitochondria become smaller in response to increased metabolic flux (49,53,59,60,85,91,99,105,107,114,124,147,158,(167)(168)(169)171) while elongating in response to starvation (68,133). Acute hyperglycemic conditions induce the formation of short and small mitochondria in a rapid response occurring in the order of minutes mediated by the fission protein DLP1 (168).…”

Section: Effects Of Diabetic Milieu On Mitochondrial Fission and Fusionmentioning

confidence: 99%

“…Phosphorylation of DLP1 at serine 616 by PKCd, Cdk1, and CDK5 has also been shown to increase the fission activity of DLP1 (132,150,151). A rapid formation of small mitochondria under acute metabolic stress causes mitochondrial ROS elevation, whereas pathologic fragmentation of mitochondria is associated with chronically elevated ROS levels and apoptotic cell death during sustained hyperglycemia (60,63,105,106,112,114,168,169).…”

Section: Effects Of Diabetic Milieu On Mitochondrial Fission and Fusionmentioning

confidence: 99%

“…Decreasing ROS levels via proton leak/uncoupling is one of the possible mechanisms by which fission inhibition may produce its beneficial effect (60). The propensity for electron slippage and free radical generation from the respiratory chain is enhanced with mitochondrial hyperpolarization, and the relief contributed by uncoupling of oxidative phosphorylation decreases ROS production (13,69,75,93,142).…”

Section: Progressive Changes Of Mitochondrial Energetics and Morpholomentioning

confidence: 99%

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Mitochondrial Dynamics in Diabetic Cardiomyopathy

Galloway

Yoon

2015

Antioxidants & Redox Signaling

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100

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Significance: Cardiac function is energetically demanding, reliant on efficient well-coupled mitochondria to generate adenosine triphosphate and fulfill the cardiac demand. Predictably then, mitochondrial dysfunction is associated with cardiac pathologies, often related to metabolic disease, most commonly diabetes. Diabetic cardiomyopathy (DCM), characterized by decreased left ventricular function, arises independently of coronary artery disease and atherosclerosis. Dysregulation of Ca 2+ handling, metabolic changes, and oxidative stress are observed in DCM, abnormalities reflected in alterations in mitochondrial energetics. Cardiac tissue from DCM patients also presents with altered mitochondrial morphology, suggesting a possible role of mitochondrial dynamics in its pathological progression. Recent Advances: Abnormal mitochondrial morphology is associated with pathologies across diverse tissues, suggesting that this highly regulated process is essential for proper cell maintenance and physiological homeostasis. Highly structured cardiac myofibers were hypothesized to limit alterations in mitochondrial morphology; however, recent work has identified morphological changes in cardiac tissue, specifically in DCM. Critical Issues: Mitochondrial dysfunction has been reported independently from observations of altered mitochondrial morphology in DCM. The temporal relationship and causative nature between functional and morphological changes of mitochondria in the establishment/progression of DCM is unclear. Future Directions: Altered mitochondrial energetics and morphology are not only causal for but also consequential to reactive oxygen species production, hence exacerbating oxidative damage through reciprocal amplification, which is integral to the progression of DCM. Therefore, targeting mitochondria for DCM will require better mechanistic characterization of morphological distortion and bioenergetic dysfunction. Antioxid. Redox Signal. 22, 1545Signal. 22, -1562

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Transgenic Control of Mitochondrial Fission Induces Mitochondrial Uncoupling and Relieves Diabetic Oxidative Stress

Cited by 76 publications

References 51 publications

IHG-1 Increases Mitochondrial Fusion and Bioenergetic Function

IHG-1 Increases Mitochondrial Fusion and Bioenergetic Function

Deficiency in Apoptosis-Inducing Factor Recapitulates Chronic Kidney Disease via Aberrant Mitochondrial Homeostasis

Mitochondrial Dynamics in Diabetic Cardiomyopathy

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