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

Kyriakoudi, Styliana; Drousiotou, Anthi; Petrou, Petros

doi:10.3390/ijms22094617

Cited by 19 publications

(16 citation statements)

References 142 publications

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“…Studies have shown that the continuous fission and fusion of mitochondria are important for maintaining mitochondrial morphology and function ( Kyriakoudi et al, 2021 ). Mammals contain two mitofusins, namely mitofusin (Mfn)-1 and Mfn2.…”

Section: Mitochondrial Dynamics and Dysfunction In Atherosclerosismentioning

confidence: 99%

Novel Insights and Current Evidence for Mechanisms of Atherosclerosis: Mitochondrial Dynamics as a Potential Therapeutic Target

Yang

Xing

et al. 2021

Front. Cell Dev. Biol.

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Cardiovascular disease (CVD) is the main cause of death worldwide. Atherosclerosis is the underlying pathological basis of CVD. Mitochondrial homeostasis is maintained through the dynamic processes of fusion and fission. Mitochondria are involved in many cellular processes, such as steroid biosynthesis, calcium homeostasis, immune cell activation, redox signaling, apoptosis, and inflammation, among others. Under stress conditions, mitochondrial dynamics, mitochondrial cristae remodeling, and mitochondrial ROS (mitoROS) production increase, mitochondrial membrane potential (MMP) decreases, calcium homeostasis is imbalanced, and mitochondrial permeability transition pore open (mPTP) and release of mitochondrial DNA (mtDNA) are activated. mtDNA recognized by TLR9 can lead to NF-κB pathway activation and pro-inflammatory factor expression. At the same time, TLR9 can also activate NLRP3 inflammasomes and release interleukin, an event that eventually leads to tissue damage and inflammatory responses. In addition, mitochondrial dysfunction may amplify the activation of NLRP3 through the production of mitochondrial ROS, which together aggravate accumulating mitochondrial damage. In addition, mtDNA defects or gene mutation can lead to mitochondrial oxidative stress. Finally, obesity, diabetes, hypertension and aging are risk factors for the progression of CVD, which are closely related to mitochondrial dynamics. Mitochondrial dynamics may represent a new target in the treatment of atherosclerosis. Antioxidants, mitochondrial inhibitors, and various new therapies to correct mitochondrial dysfunction represent a few directions for future research on therapeutic intervention and amelioration of atherosclerosis.

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Section: Mitochondrial Dynamics and Dysfunction In Atherosclerosismentioning

confidence: 99%

Novel Insights and Current Evidence for Mechanisms of Atherosclerosis: Mitochondrial Dynamics as a Potential Therapeutic Target

Yang

Xing

et al. 2021

Front. Cell Dev. Biol.

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“…Mitochondria are key organelles that produce cellular ATP and are also involved in the cell metabolic status, programmed cell death, calcium homeostasis, and the generation and control of reactive oxygen species (ROS) ( Wai and Langer, 2016 ). They are highly dynamic structures, which change their morphology and spatial distribution according to metabolic requirements, allowing cells to adapt to energy demands and maintain homeostasis ( Kyriakoudi et al, 2021 ). This changeable and adaptable nature, known as mitochondrial dynamics, includes both the regulation of mitochondrial architecture, mediated by the fusion and fission, and the movement of mitochondria along the cytoskeleton ( Chan, 2006 ).…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Dynamics and Mitochondria-Lysosome Contacts in Neurogenetic Diseases

et al. 2022

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Mitochondrial network is constantly in a dynamic and regulated balance of fusion and fission processes, which is known as mitochondrial dynamics. Mitochondria make physical contacts with almost every other membrane in the cell thus impacting cellular functions. Mutations in mitochondrial dynamics genes are known to cause neurogenetic diseases. To better understand the consequences on the cellular phenotype and pathophysiology of neurogenetic diseases associated with defective mitochondrial dynamics, we have compared the fibroblasts phenotypes of (i) patients carrying pathogenic variants in genes involved in mitochondrial dynamics such as DRP1 (also known as DNM1L), GDAP1, OPA1, and MFN2, and (ii) patients carrying mutated genes that their dysfunction affects mitochondria or induces a mitochondrial phenotype, but that are not directly involved in mitochondrial dynamic network, such as FXN (encoding frataxin, located in the mitochondrial matrix), MED13 (hyperfission phenotype), and CHKB (enlarged mitochondria phenotype). We identified mitochondrial network alterations in all patients’ fibroblasts except for CHKBQ198*/Q198*. Functionally, all fibroblasts showed mitochondrial oxidative stress, without membrane potential abnormalities. The lysosomal area and distribution were abnormal in GDAP1W67L/W67L, DRP1K75E/+, OPA1F570L/+, and FXNR165C/GAA fibroblasts. These lysosomal alterations correlated with mitochondria-lysosome membrane contact sites (MCSs) defects in GDAP1W67L/W67L exclusively. The study of mitochondrial contacts in all samples further revealed a significant decrease in MFN2R104W/+ fibroblasts. GDAP1 and MFN2 are outer mitochondrial membrane (OMM) proteins and both are related to Charcot-Marie Tooth neuropathy. Here we identified their constitutive interaction as well as MFN2 interaction with LAMP-1. Therefore MFN2 is a new mitochondria-lysosome MCSs protein. Interestingly, GDAP1W67L/W67L and MFN2R104W/+ fibroblasts carry pathogenic changes that occur in their catalytic domains thus suggesting a functional role of GDAP1 and MFN2 in mitochondria–lysosome MCSs. Finally, we observed starvation-induced autophagy alterations in DRP1K75E/+, GDAP1W67L/W67L, OPA1F570L/+, MFN2R104W/+, and CHKBQ198*/Q198* fibroblasts. These genes are related to mitochondrial membrane structure or lipid composition, which would associate the OMM with starvation-induced autophagy. In conclusion, the study of mitochondrial dynamics and mitochondria-lysosome axis in a group of patients with different neurogenetic diseases has deciphered common and unique cellular phenotypes of degrading and non-degrading pathways that shed light on pathophysiological events, new biomarkers and pharmacological targets for these disorders.

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“…In obesity, mitochondrial dynamics are disrupted. Mitochondrial dynamics depend on the availability of nutrients and energy consumption of cells [89] . It is known that, with nutrient deficiency and increased energy consumption, the mitochondrial network becomes elongated, while an abundant supply of nutrients and a decrease in energy requirements are associated with mitochondrial fragmentation [90] .…”

Section: Mitochondrial Dynamics In Metabolic and Some Inflammatory Di...mentioning

confidence: 99%

Features of mitochondrial dynamics in monocytes in inflammatory and metabolic disorders

Tolstik¹,

Bogatyreva²,

Grechko³

et al. 2022

Vessel Plus

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Mitochondria do not exist as separate formations in the cell; they form a homogeneous network in which the processes of division and fusion continuously occur. A shift in this balance, as well as mitochondrial dysfunction, leads to the development of chronic and metabolic disorders. Metabolic changes in mitochondria control the formation and differentiation of monocytes. Pro-inflammatory activation of monocytes/macrophages leads to a decrease in oxidative phosphorylation and an increase in mitochondrial fusion. To date, the molecular mechanisms that regulate mitochondrial dynamics to control life and death in monocytes are not well understood. In addition, there is ample evidence that abnormal mitochondrial metabolism is involved in the pathogenesis of many diseases. Mitochondrial stress and damage contribute to cell death, metabolic disorders, and inflammation. In this review, we consider in detail the involvement of mitochondrial processes in the development of pathologies and discuss how mitochondria can be therapeutically affected. Attention is also drawn to possible diagnostic studies that target mitochondrial dynamics of disorders in monocytes.

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

Cited by 19 publications

References 142 publications

Novel Insights and Current Evidence for Mechanisms of Atherosclerosis: Mitochondrial Dynamics as a Potential Therapeutic Target

Novel Insights and Current Evidence for Mechanisms of Atherosclerosis: Mitochondrial Dynamics as a Potential Therapeutic Target

Mitochondrial Dynamics and Mitochondria-Lysosome Contacts in Neurogenetic Diseases

Features of mitochondrial dynamics in monocytes in inflammatory and metabolic disorders

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