Mitofusin-2: Functional switch between mitochondrial function and neurodegeneration

Kulkarni, Prakash G.; Mohire, Vaibhavi M; Bhaisa, Pooja K; Joshi, Mrudula M; Puranik, Chitranshi M; Waghmare, Pranjal P; Banerjee, Tanushree

doi:10.1016/j.mito.2023.02.001

Cited by 8 publications

(2 citation statements)

References 130 publications

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“…The process of mitochondrial fission remains a hot topic of research because the involvement of proteins in the processes and their further interaction at mitochondria-endoplasmic reticulum contact sites is still to be elucidated. The mutation and deficiency of proteins involved in the fusion and fission of mitochondria can play an eminent role in the pathophysiology of several chronic diseases [10]. The process of mitochondrial fission crucially maintains mitochondrial respiration, as apart from its role in division of mitochondria, it is also employed in the waste disposal system of the mitochondria.…”

Section: The Mitochondrial Life Cycle: Fusion Fission and Autophagymentioning

confidence: 99%

Mitochondrial Dysfunction: A Cellular and Molecular Hub in Pathology of Metabolic Diseases and Infection

Behl

Makkar

Anwer

et al. 2023

JCM

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Mitochondria are semiautonomous doubly membraned intracellular components of cells. The organelle comprises of an external membrane, followed by coiled structures within the membrane called cristae, which are further surrounded by the matrix spaces followed by the space between the external and internal membrane of the organelle. A typical eukaryotic cell contains thousands of mitochondria within it, which make up 25% of the cytoplasm present in the cell. The organelle acts as a common point for the metabolism of glucose, lipids, and glutamine. Mitochondria chiefly regulate oxidative phosphorylation-mediated aerobic respiration and the TCA cycle and generate energy in the form of ATP to fulfil the cellular energy needs. The organelle possesses a unique supercoiled doubly stranded mitochondrial DNA (mtDNA) which encodes several proteins, including rRNA and tRNA crucial for the transport of electrons, oxidative phosphorylation, and initiating genetic repair processors. Defects in the components of mitochondria act as the principal factor for several chronic cellular diseases. The dysfunction of mitochondria can cause a malfunction in the TCA cycle and cause the leakage of the electron respiratory chain, leading to an increase in reactive oxygen species and the signaling of aberrant oncogenic and tumor suppressor proteins, which further alter the pathways involved in metabolism, disrupt redox balance, and induce endurance towards apoptosis and several treatments which play a major role in developing several chronic metabolic conditions. The current review presents the knowledge on the aspects of mitochondrial dysfunction and its role in cancer, diabetes mellitus, infections, and obesity.

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Section: The Mitochondrial Life Cycle: Fusion Fission and Autophagymentioning

confidence: 99%

Mitochondrial Dysfunction: A Cellular and Molecular Hub in Pathology of Metabolic Diseases and Infection

Behl

Makkar

Anwer

et al. 2023

JCM

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“…Damaged mitochondria releases reactive oxide species and mitochondrial DNA (mtDNA) into cytoplasm, which contributes to cell senescence and the progression of PD [ 13 , 14 ]. As an outer mitochondrial membrane protein, mitofusin 2 (Mfn2) plays important roles in normalizing mitochondrial homeostasis through controlling the process of fission and fusion [ 15 , 16 ]. Recently, Mfn2 has been demonstrated to participate in regulating cellular energy metabolism such as insulin resistance and glucose metabolism [ 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

Metformin normalizes mitochondrial function to delay astrocyte senescence in a mouse model of Parkinson’s disease through Mfn2-cGAS signaling

Wang,

Tian,

Zhou

et al. 2024

J Neuroinflammation

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Background Senescent astrocytes play crucial roles in age-associated neurodegenerative diseases, including Parkinson’s disease (PD). Metformin, a drug widely used for treating diabetes, exerts longevity effects and neuroprotective activities. However, its effect on astrocyte senescence in PD remains to be defined. Methods Long culture-induced replicative senescence model and 1-methyl-4-phenylpyridinium/α-synuclein aggregate-induced premature senescence model, and a mouse model of PD were used to investigate the effect of metformin on astrocyte senescence in vivo and in vitro. Immunofluorescence staining and flow cytometric analyses were performed to evaluate the mitochondrial function. We stereotactically injected AAV carrying GFAP-promoter-cGAS-shRNA to mouse substantia nigra pars compacta regions to specifically reduce astrocytic cGAS expression to clarify the potential molecular mechanism by which metformin inhibited the astrocyte senescence in PD. Results We showed that metformin inhibited the astrocyte senescence in vitro and in PD mice. Mechanistically, metformin normalized mitochondrial function to reduce mitochondrial DNA release through mitofusin 2 (Mfn2), leading to inactivation of cGAS-STING, which delayed astrocyte senescence and prevented neurodegeneration. Mfn2 overexpression in astrocytes reversed the inhibitory role of metformin in cGAS-STING activation and astrocyte senescence. More importantly, metformin ameliorated dopamine neuron injury and behavioral deficits in mice by reducing the accumulation of senescent astrocytes via inhibition of astrocytic cGAS activation. Deletion of astrocytic cGAS abolished the suppressive effects of metformin on astrocyte senescence and neurodegeneration. Conclusions This work reveals that metformin delays astrocyte senescence via inhibiting astrocytic Mfn2-cGAS activation and suggest that metformin is a promising therapeutic agent for age-associated neurodegenerative diseases.

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DNA Methylation-Mediated Mfn2 Gene Regulation in the Brain: A Role in Brain Trauma-Induced Mitochondrial Dysfunction and Memory Deficits

Kulkarni,

Balasubramanian,

Manjrekar

et al. 2023

Cell Mol Neurobiol

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Mitofusin-2: Functional switch between mitochondrial function and neurodegeneration

Cited by 8 publications

References 130 publications

Mitochondrial Dysfunction: A Cellular and Molecular Hub in Pathology of Metabolic Diseases and Infection

Mitochondrial Dysfunction: A Cellular and Molecular Hub in Pathology of Metabolic Diseases and Infection

Metformin normalizes mitochondrial function to delay astrocyte senescence in a mouse model of Parkinson’s disease through Mfn2-cGAS signaling

DNA Methylation-Mediated Mfn2 Gene Regulation in the Brain: A Role in Brain Trauma-Induced Mitochondrial Dysfunction and Memory Deficits

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