Redox Regulation of Mitochondrial Fission Protein Drp1 by Protein Disulfide Isomerase Limits Endothelial Senescence

Kim, Young-Mee; Youn, Seock Won; Varadarajan, Sudhahar; Das, Archita; Chandhri, Reyhaan; Cuervo, Henar; Kweon, Junghun; Leanhart, Silvia; He, Lin; Tóth, Péter T.; Kitajewski, Jan; Rehman, Jalees; Yoon, Yisang; Cho, Jaehyung; Fukai, Tohru; Ushio‐Fukai, Masuko

doi:10.1016/j.celrep.2018.05.054

Cited by 113 publications

(90 citation statements)

References 50 publications

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“…An increase in fragmented mitochondria also leads to increased ROS levels (Jezek et al, 2018), as confirmed by our results. Moreover, disruption of fusion proteins can also lead to an increase in ROS levels (Kim et al, 2018), as also evident in our cell model. While we did not observe any change in fission protein expression, decreased MFN2 is also consistent with the smaller, fragmented mitochondria we observed, similar to those seen in diabetic mouse coronary ECs (Makino et al, 2010).…”

Section: Discussionsupporting

confidence: 77%

Heme synthesis inhibition blocks angiogenesis via mitochondrial dysfunction

Shetty

Sishtla

Park

et al. 2019

Preprint

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The relationship between heme metabolism and angiogenesis is poorly understood. The final synthesis of heme occurs in mitochondria, where ferrochelatase (FECH) inserts Fe 2+ into protoporphyrin IX to produce proto-heme IX. We previously showed that FECH inhibition is antiangiogenic in human retinal microvascular endothelial cells (HRECs) and in animal models of ocular neovascularization. In the present study, we sought to understand the mechanism of how FECH and thus heme is involved in endothelial cell function. Mitochondria in endothelial cells had several defects in function after heme inhibition. FECH loss changed the shape and mass of mitochondria and led to significant oxidative stress. Oxidative phosphorylation and mitochondrial Complex IV were decreased in HRECs and in murine retina ex vivo after heme depletion. Supplementation with heme partially rescued phenotypes of FECH blockade. These findings provide an unexpected link between mitochondrial heme metabolism and angiogenesis.

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Section: Discussionsupporting

confidence: 77%

Heme synthesis inhibition blocks angiogenesis via mitochondrial dysfunction

Shetty

Sishtla

Park

et al. 2019

Preprint

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“…This protection might be exerted by sharing ROS-induced damage and/or mitochondrial antioxidants between individual mitochondria by stimulating fusion between ''damaged'' and ''healthy'' organelles (281). Recently, it was demonstrated that protein disulfide isomerase A1 (PDIA1) can function as a DRP1 thiol reductase (176). PDIA1 depletion stimulates DRP1 sulfenylation, thereby stimulating mitochondrial fragmentation.…”

Section: Stimulating Fusion By Drp1 Phosphorylation At S637mentioning

confidence: 99%

Mitochondrial Morphofunction in Mammalian Cells

Bulthuis

Adjobo‐Hermans

Willems

et al. 2019

Antioxidants & Redox Signaling

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Significance: In addition to their classical role in cellular ATP production, mitochondria are of key relevance in various (patho)physiological mechanisms including second messenger signaling, neuro-transduction, immune responses and death induction. Recent Advances: Within cells, mitochondria are motile and display temporal changes in internal and external structure (''mitochondrial dynamics''). During the last decade, substantial empirical and in silico evidence was presented demonstrating that mitochondrial dynamics impacts on mitochondrial function and vice versa. Critical Issues: However, a comprehensive and quantitative understanding of the bidirectional links between mitochondrial external shape, internal structure and function (''morphofunction'') is still lacking. The latter particularly hampers our understanding of the functional properties and behavior of individual mitochondrial within single living cells. Future Directions: In this review we discuss the concept of mitochondrial morphofunction in mammalian cells, primarily using experimental evidence obtained within the last decade. The topic is introduced by briefly presenting the central role of mitochondria in cell physiology and the importance of the mitochondrial electron transport chain (ETC) therein. Next, we summarize in detail how mitochondrial (ultra)structure is controlled and discuss empirical evidence regarding the equivalence of mitochondrial (ultra)structure and function. Finally, we provide a brief summary of how mitochondrial morphofunction can be quantified at the level of single cells and mitochondria, how mitochondrial ultrastructure/volume impacts on mitochondrial bioreactions and intramitochondrial protein diffusion, and how mitochondrial morphofunction can be targeted by small molecules.

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“…Evidence suggests that mitochondrial morphology is tightly coupled to ROS generation depending on the physiological state of the cell (Yu, Robotham, & Yoon, ). Accumulation of ROS results in a shift to a more fragmented population of mitochondria (Kim et al, ; Willems, Rossignol, Dieteren, Murphy, & Koopman, ). We showed that NMN is decreasing SOD2 acetylation via SIRT3, which leads to reduced hippocampal ROS levels.…”

Section: Resultsmentioning

confidence: 99%

Nicotinamide mononucleotide alters mitochondrial dynamics by SIRT3‐dependent mechanism in male mice

Klimova

Long

Kristián

2019

J of Neuroscience Research

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Nicotinamide adenine dinucleotide (NAD+) is a central signaling molecule and enzyme cofactor that is involved in a variety of fundamental biological processes. NAD+ levels decline with age, neurodegenerative conditions, acute brain injury, and in obesity or diabetes. Loss of NAD+ results in impaired mitochondrial and cellular functions. Administration of NAD+ precursor, nicotinamide mononucleotide (NMN), has shown to improve mitochondrial bioenergetics, reverse age‐associated physiological decline, and inhibit postischemic NAD+ degradation and cellular death. In this study, we identified a novel link between NAD+ metabolism and mitochondrial dynamics. A single dose (62.5 mg/kg) of NMN, administered to male mice, increases hippocampal mitochondria NAD+ pools for up to 24 hr posttreatment and drives a sirtuin 3 (SIRT3)‐mediated global decrease in mitochondrial protein acetylation. This results in a reduction of hippocampal reactive oxygen species levels via SIRT3‐driven deacetylation of mitochondrial manganese superoxide dismutase. Consequently, mitochondria in neurons become less fragmented due to lower interaction of phosphorylated fission protein, dynamin‐related protein 1 (pDrp1 [S616]), with mitochondria. In conclusion, manipulation of mitochondrial NAD+ levels by NMN results in metabolic changes that protect mitochondria against reactive oxygen species and excessive fragmentation, offering therapeutic approaches for pathophysiologic stress conditions.

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Redox Regulation of Mitochondrial Fission Protein Drp1 by Protein Disulfide Isomerase Limits Endothelial Senescence

Cited by 113 publications

References 50 publications

Heme synthesis inhibition blocks angiogenesis via mitochondrial dysfunction

Heme synthesis inhibition blocks angiogenesis via mitochondrial dysfunction

Mitochondrial Morphofunction in Mammalian Cells

Nicotinamide mononucleotide alters mitochondrial dynamics by SIRT3‐dependent mechanism in male mice

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