Modulation of Dynamin-related Protein 1 (DRP1) Function by Increased O-linked-β-N-acetylglucosamine Modification (O-GlcNAc) in Cardiac Myocytes

Gawlowski, Thomas; Suárez, Jorge; Scott, Brian T.; Torres-Gonzalez, Moises; Wang, Hong; Schwappacher, Raphaela; Han, Xuemei; Yates, John R.; Hoshijima, Masahiko; Dillmann, Wolfgang H.

doi:10.1074/jbc.m112.390682

Cited by 170 publications

(151 citation statements)

References 46 publications

Supporting

Mentioning

150

Contrasting

Order By: Relevance

“…The mitochondrial membrane potential was measured by JC-1 as described previously (17). Briefly, H9C2 cells were loaded with 0.5 mM JC-1 at 37°C for 15 min and washed three times with media.…”

Section: Methodsmentioning

confidence: 99%

“…After menadione treatment, the mitochondrial morphology was observed. Cells were stained with 10 Ϫ7 M MitoTracker Green FM for 30 min to visualize mitochondrial morphology and then washed 3 times with media (17). Images were captured with a DeltaVision deconvolution microscope system (Applied Precision) located at the University of California, San Diego Cancer Center microscope facility.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Mitochondrial 8-oxoguanine glycosylase decreases mitochondrial fragmentation and improves mitochondrial function in H9C2 cells under oxidative stress conditions

Torres-Gonzalez

Gawlowski

Kocalis

et al. 2014

American Journal of Physiology-Cell Physiology

Self Cite

View full text Add to dashboard Cite

The mitochondrial DNA base modification 8-hydroxy 2=-deoxyguanine (8-OHdG) is one of the most common DNA lesions induced by reactive oxygen species (ROS) and is considered an index of DNA damage. High levels of mitochondrial 8-OHdG have been correlated with increased mutation, deletion, and loss of mitochondrial (mt) DNA, as well as apoptosis. 8-Oxoguanosine DNA glycosylase-1 (OGG1) recognizes and removes 8-OHdG to prevent further DNA damage. We evaluated the effects of OGG1 on mtDNA damage, mitochondrial function, and apoptotic events induced by oxidative stress using H9C2 cardiac cells treated with menadione and transduced with either Adv-Ogg1 or Adv-Control (empty vector). The levels of mtDNA 8-OHdG and the presence of apurinic/apyrimidinic (AP) sites were decreased by 30% and 35%, respectively, in Adv-Ogg1 transduced cells (P Ͻ 0.0001 and P Ͻ 0.005, respectively). In addition, the expression of base excision repair (BER) pathway members APE1 and DNA polymerase ␥ was upregulated by Adv-Ogg1 transduction. Cells overexpressing Ogg1 had increased membrane potential (P Ͻ 0.05) and decreased mitochondrial fragmentation (P Ͻ 0.005). The mtDNA content was found to be higher in cells with increased OGG1 (P Ͻ 0.005). The protein levels of fission and apoptotic factors such as DRP1, FIS1, cytoplasmic cytochrome c, activated caspase-3, and activated caspase-9 were lower in Adv-Ogg1 transduced cells. These observations suggest that Ogg1 overexpression may be an important mechanism to protect cardiac cells against oxidative stress damage.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Mitochondrial 8-oxoguanine glycosylase decreases mitochondrial fragmentation and improves mitochondrial function in H9C2 cells under oxidative stress conditions

Torres-Gonzalez

Gawlowski

Kocalis

et al. 2014

American Journal of Physiology-Cell Physiology

Self Cite

View full text Add to dashboard Cite

show abstract

“…We and Zucker et al (2011) (Briones et al 2001;Burnham-Marusich & Berninsone, 2012;Gao et al 2002;Gawlowski et al 2012). …”

Section: Discussionmentioning

confidence: 87%

Ultrastructural Analysis of Zebra Fish (Daniorerio) DHDDS Retinitis Pigmentosa Disease Model Functionally Links DHDDS to Mitochondrial and Membrane Dysfunction

Prince¹,

Dallman²,

Miyazaki³

et al. 2016

AIJB

View full text Add to dashboard Cite

A mutation in the enzyme dehydrodolichyldiphosphate synthase (DHDDS) has been causally linked to human retinitis pigmentosa (RP), a disease associated with late onset blindness due to loss of photoreceptors in the eye. Indeed, knock-down models of DHDDS in zebrafish are blind with reduced or absent photoreceptor outer segments, confirming the causal relationship between DHDDS and vision. To address mechanisms by which DHDDS knock-down disrupts photoreceptor outer segments, we used electron microscopy to examine the ultra structure of the retina at two developmental stages, one before (31 hours post-fertilization, hpf) and the other after (104 hpf) outer segments and associated vision normally develop. We identify at least three different ultra structural traits that distinguished mitochonrdria in DHDDS knock-down and control fish at both time points suggesting that early mitochondrial dysfunction may underlie the later deficits in the development of photoreceptor outer segments. In addition, other membrane systems (those surrounding guanine crystals in the iridophore layer and melanin pigment granules in the pigmented epithelial layer) were compromised.

show abstract

“…Of particular relevance to the impact of O-GlcNAcylation in the heart is the role of O-GlcNAc modification of mitochondrial proteins. For example, respiratory chain complex proteins, such as subunit NDUFA9 of complex I, subunits core 1 and core 2 of complex III, and the mitochondrial DNA-encoded subunit I of complex IV (cytochrome c oxidase 1), as well as DRP1 (dynamin-related protein 1), a regulator of mitochondrial fission, are O-GlcNAcylated in cardiomyocytes (49,50). Increased O-GlcNAcylation of these proteins has been linked to the adverse effects of hyperglycemia on mitochondrial function (49,50).…”

Section: O-glcnacylation and The Heartmentioning

confidence: 99%

“…For example, respiratory chain complex proteins, such as subunit NDUFA9 of complex I, subunits core 1 and core 2 of complex III, and the mitochondrial DNA-encoded subunit I of complex IV (cytochrome c oxidase 1), as well as DRP1 (dynamin-related protein 1), a regulator of mitochondrial fission, are O-GlcNAcylated in cardiomyocytes (49,50). Increased O-GlcNAcylation of these proteins has been linked to the adverse effects of hyperglycemia on mitochondrial function (49,50). Hearts from rats with a low running capacity have higher O-GlcNAcylation of complexes I and IV and the voltagedependent anion channel (VDAC) compared with those from rats with a high running capacity (51).…”

Section: O-glcnacylation and The Heartmentioning

confidence: 99%

Protein O-GlcNAcylation and Cardiovascular (Patho)physiology

Marsh

Collins

Chatham

2014

Journal of Biological Chemistry

View full text Add to dashboard Cite

Our understanding of the role of protein O-GlcNAcylation in the regulation of the cardiovascular system has increased rapidly in recent years. Studies have linked increased O-GlcNAc levels to glucose toxicity and diabetic complications; conversely, acute activation of O-GlcNAcylation has been shown to be cardioprotective. However, it is also increasingly evident that O-GlcNAc turnover plays a central role in the delicate regulation of the cardiovascular system. Therefore, the goals of this minireview are to summarize our current understanding of how changes in O-GlcNAcylation influence cardiovascular pathophysiology and to highlight the evidence that O-GlcNAc cycling is critical for normal function of the cardiovascular system.The O-linked attachment of ␤-N-acetylglucosamine (O-GlcNAc) to serine/threonine residues of proteins is a dynamic, transient, and reversible process that is an essential, metabolically regulated, signal transduction mediator in all cells (1). O-GlcNAc transferase (OGT) 3 catalyzes O-GlcNAc formation, utilizing UDP-GlcNAc as the substrate. UDPGlcNAc is the end product of the hexosamine biosynthesis pathway (HBP), which is regulated primarily by L-glutamine:Dfructose-6-phosphate amidotransferase (GFAT). GFAT catalyzes the formation of glucosamine 6-phosphate from fructose 6-phosphate. It has been estimated that 2-5% of glucose entering glycolysis is diverted through GFAT, thereby contributing to UDP-GlcNAc and O-GlcNAc synthesis (2); however, quantitative analysis of glucose flux via the HBP in the heart has yet to be performed. Although glucose availability is an important factor in O-GlcNAc synthesis, glutamine is critical as the amine donor for glucosamine 6-phosphate, whereas fatty acid metabolism is likely the primary source for the acetyl moiety. Thus, multiple nutrients contribute to both UDP-GlcNAc and protein O-GlcNAc synthesis. In addition to its synthesis, the levels of protein O-GlcNAc are also regulated by the activity of ␤-Nacetylhexosaminidase (O-GlcNAcase (OGA)), which catalyzes removal of this post-translational modification.A little over a decade following the identification of O-GlcNAc protein modification by Torres and Hart (3), the small heat shock protein ␣B-crystallin was shown to be an O-GlcNAc target in rat heart (4). Using vascular smooth muscle cells, Han and Kudlow (5) demonstrated in 1997 that O-GlcNAcylation of the transcription factor Sp1 modulated its susceptibility to proteasomal degradation, concluding that this may provide a link between nutritional status and transcriptional regulation. In the same year, reported that OGT activity was significantly higher in rat heart compared with liver, fat, and other types of striated muscle; they also hypothesized that O-GlcNAcylation could be involved in mediating glucose toxicity in insulin-responsive tissues. To our knowledge, these were the first reports of O-GlcNAcylated proteins in cardiac or vascular tissues, as well as the first to suggest that protein O-GlcNAcylation may contribute to the adverse effects of i...

show abstract

Modulation of Dynamin-related Protein 1 (DRP1) Function by Increased O-linked-β-N-acetylglucosamine Modification (O-GlcNAc) in Cardiac Myocytes

Cited by 170 publications

References 46 publications

Mitochondrial 8-oxoguanine glycosylase decreases mitochondrial fragmentation and improves mitochondrial function in H9C2 cells under oxidative stress conditions

Mitochondrial 8-oxoguanine glycosylase decreases mitochondrial fragmentation and improves mitochondrial function in H9C2 cells under oxidative stress conditions

Ultrastructural Analysis of Zebra Fish (Daniorerio) DHDDS Retinitis Pigmentosa Disease Model Functionally Links DHDDS to Mitochondrial and Membrane Dysfunction

Protein O-GlcNAcylation and Cardiovascular (Patho)physiology

Contact Info

Product

Resources

About