Mitochondrial fusion promoter restores mitochondrial dynamics balance and ameliorates diabetic cardiomyopathy in an optic atrophy 1‐dependent way

Mitochondria are highly dynamic, complex organelles that continuously alter their shape, ranging between two opposite processes, fission and fusion, in response to several stimuli and the metabolic demands of the cell. Alterations in mitochondrial dynamics due to mutations in proteins involved in the fusion-fission machinery represent an important pathogenic mechanism of human diseases. The most relevant proteins involved in the mitochondrial fusion process are three GTPase dynamin-like proteins: mitofusin 1 (MFN1) and 2 (MFN2), located in the outer mitochondrial membrane, and optic atrophy protein 1 (OPA1), in the inner membrane. An expanding number of degenerative disorders are associated with mutations in the genes encoding MFN2 and OPA1, including Charcot-Marie-Tooth disease type 2A and autosomal dominant optic atrophy. While these disorders can still be considered rare, defective mitochondrial dynamics seem to play a significant role in the molecular and cellular pathogenesis of more common neurodegenerative diseases, for example, Alzheimer’s and Parkinson’s diseases. This review provides an overview of the basic molecular mechanisms involved in mitochondrial fusion and focuses on the alteration in mitochondrial DNA amount resulting from impairment of mitochondrial dynamics. We also review the literature describing the main disorders associated with the disruption of mitochondrial fusion.

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Faculty Opinions recommendation of Quantitation of mitochondrial dynamics by photolabeling of individual organelles shows that mitochondrial fusion is blocked during the Bax activation phase of apoptosis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1017366.203171 ◽

2004 ◽

Author(s):

David Andrews

Keyword(s):

Mitochondrial Dynamics ◽

Mitochondrial Fusion ◽

Activation Phase

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Glucose limitation activates AMPK coupled SENP1-Sirt3 signalling in mitochondria for T cell memory development

Nature Communications ◽

10.1038/s41467-021-24619-2 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Jianli He ◽

Xun Shangguan ◽

Wei Zhou ◽

Ying Cao ◽

Quan Zheng ◽

...

Keyword(s):

T Cell ◽

Mitochondrial Dynamics ◽

Mitochondrial Fusion ◽

Metabolic Reprogramming ◽

Negative Regulator ◽

T Cell Memory ◽

Memory Development ◽

Cell Memory ◽

Glucose Limitation ◽

Glycolytic Intermediate

AbstractMetabolic programming and mitochondrial dynamics along with T cell differentiation affect T cell fate and memory development; however, how to control metabolic reprogramming and mitochondrial dynamics in T cell memory development is unclear. Here, we provide evidence that the SUMO protease SENP1 promotes T cell memory development via Sirt3 deSUMOylation. SENP1-Sirt3 signalling augments the deacetylase activity of Sirt3, promoting both OXPHOS and mitochondrial fusion. Mechanistically, SENP1 activates Sirt3 deacetylase activity in T cell mitochondria, leading to reduction of the acetylation of mitochondrial metalloprotease YME1L1. Consequently, deacetylation of YME1L1 suppresses its activity on OPA1 cleavage to facilitate mitochondrial fusion, which results in T cell survival and promotes T cell memory development. We also show that the glycolytic intermediate fructose-1,6-bisphosphate (FBP) as a negative regulator suppresses AMPK-mediated activation of the SENP1-Sirt3 axis and reduces memory development. Moreover, glucose limitation reduces FBP production and activates AMPK during T cell memory development. These data show that glucose limitation activates AMPK and the subsequent SENP1-Sirt3 signalling for T cell memory development.

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When the Balance Tips: Dysregulation of Mitochondrial Dynamics as a Culprit in Disease

International Journal of Molecular Sciences ◽

10.3390/ijms22094617 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4617

Author(s):

Styliana Kyriakoudi ◽

Anthi Drousiotou ◽

Petros P. Petrou

Keyword(s):

Insulin Resistance ◽

Mitochondrial Function ◽

Human Disease ◽

Molecular Mechanisms ◽

Mitochondrial Dynamics ◽

Mitochondrial Fusion ◽

Mitochondrial Morphology ◽

Disease Development ◽

Pathological Conditions ◽

Wide Range

Mitochondria are dynamic organelles, the morphology of which is tightly linked to their functions. The interplay between the coordinated events of fusion and fission that are collectively described as mitochondrial dynamics regulates mitochondrial morphology and adjusts mitochondrial function. Over the last few years, accruing evidence established a connection between dysregulated mitochondrial dynamics and disease development and progression. Defects in key components of the machinery mediating mitochondrial fusion and fission have been linked to a wide range of pathological conditions, such as insulin resistance and obesity, neurodegenerative diseases and cancer. Here, we provide an update on the molecular mechanisms promoting mitochondrial fusion and fission in mammals and discuss the emerging association of disturbed mitochondrial dynamics with human disease.

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Nanoscopic quantification of sub-mitochondrial morphology, mitophagy and mitochondrial dynamics in living cells derived from patients with mitochondrial diseases

Journal of Nanobiotechnology ◽

10.1186/s12951-021-00882-9 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Weiwei Zou ◽

Qixin Chen ◽

Jesse Slone ◽

Li Yang ◽

Xiaoting Lou ◽

...

Keyword(s):

Oxidative Phosphorylation ◽

Optic Atrophy ◽

Respiratory Function ◽

Clinical Symptoms ◽

Mitochondrial Dynamics ◽

Cerebellar Atrophy ◽

Mitochondrial Diseases ◽

Living Cells ◽

Mitochondrial Morphology ◽

Mitochondrial Oxidative Phosphorylation

AbstractSLC25A46 mutations have been found to lead to mitochondrial hyper-fusion and reduced mitochondrial respiratory function, which results in optic atrophy, cerebellar atrophy, and other clinical symptoms of mitochondrial disease. However, it is generally believed that mitochondrial fusion is attributable to increased mitochondrial oxidative phosphorylation (OXPHOS), which is inconsistent with the decreased OXPHOS of highly-fused mitochondria observed in previous studies. In this paper, we have used the live-cell nanoscope to observe and quantify the structure of mitochondrial cristae, and the behavior of mitochondria and lysosomes in patient-derived SLC25A46 mutant fibroblasts. The results show that the cristae have been markedly damaged in the mutant fibroblasts, but there is no corresponding increase in mitophagy. This study suggests that severely damaged mitochondrial cristae might be the predominant cause of reduced OXPHOS in SLC25A46 mutant fibroblasts. This study demonstrates the utility of nanoscope-based imaging for realizing the sub-mitochondrial morphology, mitophagy and mitochondrial dynamics in living cells, which may be particularly valuable for the quick evaluation of pathogenesis of mitochondrial morphological abnormalities.

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Interleukin-1β mediates alterations in mitochondrial fusion/fission proteins and memory impairment induced by amyloid-β oligomers

Journal of Neuroinflammation ◽

10.1186/s12974-021-02099-x ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Andre F. Batista ◽

Tayná Rody ◽

Leticia Forny-Germano ◽

Suzana Cerdeiro ◽

Maria Bellio ◽

...

Keyword(s):

Cognitive Impairment ◽

Mitochondrial Dysfunction ◽

Memory Impairment ◽

Mitochondrial Dynamics ◽

Interleukin 1 ◽

Amyloid Β ◽

Mitochondrial Fusion ◽

Synapse Loss ◽

Cynomolgus Macaques ◽

The Impact

Abstract Background The lack of effective treatments for Alzheimer’s disease (AD) reflects an incomplete understanding of disease mechanisms. Alterations in proteins involved in mitochondrial dynamics, an essential process for mitochondrial integrity and function, have been reported in AD brains. Impaired mitochondrial dynamics causes mitochondrial dysfunction and has been associated with cognitive impairment in AD. Here, we investigated a possible link between pro-inflammatory interleukin-1 (IL-1), mitochondrial dysfunction, and cognitive impairment in AD models. Methods We exposed primary hippocampal cell cultures to amyloid-β oligomers (AβOs) and carried out AβO infusions into the lateral cerebral ventricle of cynomolgus macaques to assess the impact of AβOs on proteins that regulate mitochondrial dynamics. Where indicated, primary cultures were pre-treated with mitochondrial division inhibitor 1 (mdivi-1), or with anakinra, a recombinant interleukin-1 receptor (IL-1R) antagonist used in the treatment of rheumatoid arthritis. Cognitive impairment was investigated in C57BL/6 mice that received an intracerebroventricular (i.c.v.) infusion of AβOs in the presence or absence of mdivi-1. To assess the role of interleukin-1 beta (IL-1β) in AβO-induced alterations in mitochondrial proteins and memory impairment, interleukin receptor-1 knockout (Il1r1−/−) mice received an i.c.v. infusion of AβOs. Results We report that anakinra prevented AβO-induced alteration in mitochondrial dynamics proteins in primary hippocampal cultures. Altered levels of proteins involved in mitochondrial fusion and fission were observed in the brains of cynomolgus macaques that received i.c.v. infusions of AβOs. The mitochondrial fission inhibitor, mdivi-1, alleviated synapse loss and cognitive impairment induced by AβOs in mice. In addition, AβOs failed to cause alterations in expression of mitochondrial dynamics proteins or memory impairment in Il1r1−/− mice. Conclusion These findings indicate that IL-1β mediates the impact of AβOs on proteins involved in mitochondrial dynamics and that strategies aimed to prevent pathological alterations in those proteins may counteract synapse loss and cognitive impairment in AD.

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Paeonol promotes Opa1-mediated mitochondrial fusion via activating the CK2α-Stat3 pathway in diabetic cardiomyopathy

Redox Biology ◽

10.1016/j.redox.2021.102098 ◽

2021 ◽

pp. 102098

Author(s):

Chaoyang Liu ◽

Yuehu Han ◽

Xiaoming Gu ◽

Man Li ◽

Yanyan Du ◽

...

Keyword(s):

Diabetic Cardiomyopathy ◽

Mitochondrial Fusion ◽

Stat3 Pathway

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Dynamin-related protein 1 deficiency accelerates lipopolysaccharide-induced acute liver injury and inflammation in mice

Communications Biology ◽

10.1038/s42003-021-02413-6 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Lixiang Wang ◽

Xin Li ◽

Yuki Hanada ◽

Nao Hasuzawa ◽

Yoshinori Moriyama ◽

...

Keyword(s):

Liver Disease ◽

Liver Injury ◽

Er Stress ◽

Disease Progression ◽

Acute Liver Injury ◽

Mitochondrial Dynamics ◽

Mitochondrial Fission ◽

Mitochondrial Fusion ◽

Related Protein ◽

Liver Disease Progression

AbstractMitochondrial fusion and fission, which are strongly related to normal mitochondrial function, are referred to as mitochondrial dynamics. Mitochondrial fusion defects in the liver cause a non-alcoholic steatohepatitis-like phenotype and liver cancer. However, whether mitochondrial fission defect directly impair liver function and stimulate liver disease progression, too, is unclear. Dynamin-related protein 1 (DRP1) is a key factor controlling mitochondrial fission. We hypothesized that DRP1 defects are a causal factor directly involved in liver disease development and stimulate liver disease progression. Drp1 defects directly promoted endoplasmic reticulum (ER) stress, hepatocyte death, and subsequently induced infiltration of inflammatory macrophages. Drp1 deletion increased the expression of numerous genes involved in the immune response and DNA damage in Drp1LiKO mouse primary hepatocytes. We administered lipopolysaccharide (LPS) to liver-specific Drp1-knockout (Drp1LiKO) mice and observed an increased inflammatory cytokine expression in the liver and serum caused by exaggerated ER stress and enhanced inflammasome activation. This study indicates that Drp1 defect-induced mitochondrial dynamics dysfunction directly regulates the fate and function of hepatocytes and enhances LPS-induced acute liver injury in vivo.

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362-P: Punicalagin Promotes Mitochondrial Fusion and Alleviates Diabetic Cardiomyopathy via Regulating PTP1B-Stat3-Opa1 Pathway

Diabetes ◽

10.2337/db21-362-p ◽

2021 ◽

Vol 70 (Supplement 1) ◽

pp. 362-P

Author(s):

MINGGE DING ◽

MAN LI ◽

FENG FU ◽

CHAOYANG LIU

Keyword(s):

Diabetic Cardiomyopathy ◽

Mitochondrial Fusion

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Mst1 Knockout Alleviates Mitochondrial Fission and Mitigates Left Ventricular Remodeling in the Development of Diabetic Cardiomyopathy

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.628842 ◽

2021 ◽

Vol 8 ◽

Author(s):

Xinyu Feng ◽

Shanjie Wang ◽

Xingjun Yang ◽

Jie Lin ◽

Wanrong Man ◽

...

Keyword(s):

Diabetic Cardiomyopathy ◽

Ventricular Remodeling ◽

Mitochondrial Dynamics ◽

Left Ventricular Remodeling ◽

Mitochondrial Fission ◽

Left Ventricular ◽

Neonatal Cardiomyocytes ◽

Primary Neonatal Cardiomyocytes ◽

Hemodynamic Measurements ◽

Medium Culture

The disruption of mitochondrial dynamics is responsible for the development of diabetic cardiomyopathy (DCM). However, the mechanisms that regulate the balance of mitochondrial fission and fusion are not well-understood. Wild-type, Mst1 transgenic and Mst1 knockout mice were induced with experimental diabetes by streptozotocin injection. In addition, primary neonatal cardiomyocytes were isolated and cultured to simulate diabetes to explore the mechanisms. Echocardiograms and hemodynamic measurements revealed that Mst1 knockout alleviated left ventricular remodeling and cardiac dysfunction in diabetic mice. Mst1 knockdown significantly decreased the number of TUNEL-positive cardiomyocytes subjected to high-glucose (HG) medium culture. Immunofluorescence study indicated that Mst1 overexpression enhanced, while Mst1 knockdown mitigated mitochondrial fission in DCM. Mst1 participated in the regulation of mitochondrial fission by upregulating the expression of Drp1, activating Drp1S616 phosphorylation and Drp1S637 dephosphorylation, as well as promoting Drp1 recruitment to the mitochondria. Furthermore, Drp1 knockdown abolished the effects of Mst1 on mitochondrial fission, mitochondrial membrane potential and mitochondrial dysfunction in cardiomyocytes subjected to HG treatment. These results indicated that Mst1 knockout inhibits mitochondrial fission and alleviates left ventricular remodeling thus prevents the development of DCM.

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