Alterations in mitochondrial function and cytosolic calcium induced by hyperglycemia are restored by mitochondrial transcription factor A in cardiomyocytes

Abstract

Mitochondrial transcription factor A (TFAM) is essential for mitochondrial DNA transcription and replication. TFAM transcriptional activity is decreased in diabetic cardiomyopathy; however, the functional implications are unknown. We hypothesized that a reduced TFAM activity may be responsible for some of the alterations caused by hyperglycemia. Therefore, we investigated the effect of TFAM overexpression on hyperglycemia-induced cytosolic calcium handling and mitochondrial abnormalities. Neonatal rat cardiomyocytes were exposed to high glucose (30 mM) for 48 h, and we examined whether TFAM overexpression, by protecting mitochondrial DNA, could reestablish calcium fluxes and mitochondrial alterations toward normal. Our results shown that TFAM overexpression increased to more than twofold mitochondria copy number in cells treated either with normal (5.5 mM) or high glucose. ATP content was reduced by 30% and mitochondrial calcium decreased by 40% after high glucose. TFAM overexpression returned these parameters to even higher than control values. Calcium transients were prolonged by 70% after high glucose, which was associated with diminished sarco(endo)plasmic reticulum Ca(2+)-ATPase 2a and cytochrome-c oxidase subunit 1 expression. These parameters were returned to control values after TFAM overexpression. High glucose-induced protein oxidation was reduced by TFAM overexpression, indicating a reduction of the high glucose-induced oxidative stress. In addition, we found that TFAM activity can be modulated by O-linked beta-N-acetylglucosamine glycosylation. In conclusion, TFAM overexpression protected cell function against the damage induced by high glucose in cardiomyocytes.

Diabetes-associated dysregulation of O -GlcNAcylation in rat cardiac mitochondria

“…2 F and G). It has previously been reported that high-glucose-treated cardiomyocytes show significant loss in complex IV activity (11,18). Our results directly implicate O-GlcNAcylation in the mechanism of this loss of complex IV activity.…”

“…Within the cardiovascular system, significant levels of O-GlcNAcylation have been observed on myofilament proteins, which severely affect contractile force generation (10). Alterations in cardiac O-GlcNAc levels significantly affect Ca 2+ handling and Serca2a function (11). STIM1 a modulator of cardiomyocyte calcium entry is modified by O-GlcNAc, which affects cellular calcium translocation (12).…”

Oocyte developmental failure in response to elevated nonesterified fatty acid concentrations: mechanistic insights

“…The HIGH COMBI blastocysts tended to display upregulated expression of MNSOD, an enzyme that plays a protectant role against oxidative stress (Harvey et al 1995), which might be the result of a compensatory mechanism in response to a shifted REDOX potential at earlier stages of development and in turn affect the activity of REDOX-sensitive transcription factors, a suggestion supported by our previous demonstration of SLC2A1 mRNA upregulation in HIGH COMBI embryos (Van Hoeck et al 2011). Moreover, the HIGH COMBI embryos showed higher expression of TFAM, which is essential in stabilizing mitochondrial DNA and for which overexpression is reported to be related to oxidative stress (Suarez et al 2008). Interestingly, a significant increase was also observed in the mRNA encoding enzymes involved in the fatty acid synthesis pathways; namely ACSL1 and ACCA in HIGH COMBI blastocysts.…”

The regulation of sarco(endo)plasmic reticulum calcium-ATPases (SERCA)

“…Overexpression of both TFAM and TFB2M has been demonstrated to increase transcriptional activity 2-fold, while concurrently providing protection against stressinduced reductions in SERCA2a mRNA levels (Watanabe et al 2011). Furthermore, the expression of TFAM is downregulated in the diabetic heart and in conditions of cardiac failure postmyocardial infarction (Choi et al 2001;Ikeuchi et al 2005;Suarez et al 2008a). Thus, transcription factors including TFAM and TFB2M are essential in regulating the transcription of the ATP2a2 gene.…”