Mitochondrial fission and fusion

Mitochondrial fission and fusion are important for mitochondrial function, and dynamin 1-like protein (DNM1L) is a key regulator of mitochondrial fission. We investigated the effect of mitochondrial fission on mitochondrial function and inflammation in fibroblast-like synoviocytes (FLSs) during rheumatoid arthritis (RA). DNM1L expression was determined in synovial tissues (STs) from RA and non-RA patients.FLSs were isolated from STs and treated with a DNM1L inhibitor (mdivi-1, mitochondrial division inhibitor 1) or transfected with DNM1L-specific siRNA. Mitochondrial morphology, DNM1L expression, cell viability, mitochondrial membrane potential, reactive oxygen species (ROS), apoptosis, inflammatory cytokine expression and autophagy were examined. The impact of mdivi-1 treatment on development and severity of collagen-induced arthritis (CIA) was determined in mice. Up-regulated DNM1L expression was associated with reduced mitochondrial length in STs from patients with RA and increased RA severity. Inhibition of DNM1L in FLSs triggered mitochondrial depolarization, mitochondrial elongation, decreased cell viability, production of ROS, IL-8 and COX-2, and increased apoptosis. DNM1L deficiency inhibited IL-1βmediated AKT/IKK activation, NF-κBp65 nuclear translocation and LC3B-related autophagy, but enhanced NFKBIA expression. Treatment of CIA mice with mdivi-1 decreased disease severity by modulating inflammatory cytokine and ROS production. Our major results are that up-regulated DNM1L and mitochondrial fission promoted survival, LC3B-related autophagy and ROS production in FLSs, factors that lead to inflammation by regulating AKT/IKK/NFKBIA/NF-κB signalling. Thus, inhibition of DNM1L may be a new strategy for treatment of RA. K E Y W O R D Sdynamin 1-like protein, fibroblast-like synoviocyte, inflammation, mitochondrial fission, rheumatoid arthritis | 1517 WANG et Al.

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“…MFN1 knockout mice display fragmented mitochondria 41. MFN1 knockout mice display fragmented mitochondria 41.…”

mentioning

confidence: 99%

Inhibition of DNM1L and mitochondrial fission attenuates inflammatory response in fibroblast‐like synoviocytes of rheumatoid arthritis

Wang

Chen

Fan

et al. 2019

J Cellular Molecular Medi

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“…Whether HSPB8 K141N mutants could stabilize actin and microtubules still needs further investigation. Fission and fusion are essential processes that maintain mitochondrial distribution (Patrushev et al, 2015). Cells expressing MFN mutants have aggregated mitochondria.…”

Section: Discussionmentioning

confidence: 99%

“…Defects in mitochondrial fusion/fission have been shown to decrease mitochondrial movement and caused mitochondria aggregation (Patrushev et al, 2015; Bertholet et al, 2016) and abnormal fission or fusion could directly impacts mitochondrial function, for example resulting in excessive production of free radicals, altered mitochondrial enzymatic activities (Reddy, 2014). Generation of ROS is an inevitable outcome of the redox reaction.…”

Section: Discussionmentioning

confidence: 99%

L-3-n-Butylphthalide Protects HSPB8 K141N Mutation-Induced Oxidative Stress by Modulating the Mitochondrial Apoptotic and Nrf2 Pathways

et al. 2017

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Charcot–Marie–Tooth disease (CMT), also known as hereditary motor and sensory neuropathy, is the most common inherited peripheral nerve disorder. Missense mutations, such as K141N, in the small heat shock protein HSPB8 are known to cause distal hereditary motor neuropathy 2A (dHMN2A) or Charcot-Marie-Tooth neuropathy type 2L (CMT2L). However, of critical clinical significance, very few specific therapies for this disease exist. In the present study, we investigated the impact of mutant K141N HSPB8 on mitochondrial distribution and function in a cellular model of CMT2L. Our results indicate that K141N HSPB8 induced mitochondrial aggregation and caused increased oxidative stress injury. As an extraction from Chinese celery Apium graveolens Linn seeds, L-3-n-Butylphthalide (NBP), has been reported to exert many neuroprotective effects, we interrogated whether NBP could elicit a protective effect on the cell injury typically caused by HSPB8 K141N mutations. We found NBP could reverse the pathological processes induced by HSPB8 K141N mutation via an antioxidant effect, modulation of the Bax/Bcl-2 mitochondrial apoptotic and Nrf2 pathways. We propose a novel function of HSPB8, highlighting the consequence of the K141N pathogenic mutation. Furthermore, we suggest NBP may have promising therapeutic potential in the treatment of CMT2L.

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“…PM 2.5 exposure causes mitochondrial dysfunction and DNA damage in lung tissues and triggers a systemic inflammatory process (Guo et al, 2017;Li et al, 2015b;Zhang et al, 2018). In mammalian cells, mitochondrial structure is regulated by the fusion and fission process (Patrushev et al, 2015). Mitochondrial fusion is mainly driven by Mfn1/2 in the outer membrane and by OPA1 in the inner membrane (Szabo et al, 2018).…”

Section: Mapkmentioning

confidence: 99%

Protective effects of VGX-1027 in PM2.5-induced airway inflammation and bronchial hyperresponsiveness

Wang

et al. 2019

European Journal of Pharmacology

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Mitochondrial fission and fusion

Cited by 22 publications

References 71 publications

Inhibition of DNM1L and mitochondrial fission attenuates inflammatory response in fibroblast‐like synoviocytes of rheumatoid arthritis

Inhibition of DNM1L and mitochondrial fission attenuates inflammatory response in fibroblast‐like synoviocytes of rheumatoid arthritis

L-3-n-Butylphthalide Protects HSPB8 K141N Mutation-Induced Oxidative Stress by Modulating the Mitochondrial Apoptotic and Nrf2 Pathways

Protective effects of VGX-1027 in PM2.5-induced airway inflammation and bronchial hyperresponsiveness

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