Drp1, a potential therapeutic target for Parkinson’s disease, is involved in olfactory bulb pathological alteration in the Rotenone-induced rat model

Experimental Dermatology

et al. 2021

Atopic dermatitis (AD) is a chronic inflammatory cutaneous disorder with few treatment options. Dynamin‐related protein 1 (Drp1)‐dependent mitochondrial fission contributes to the activation of NLRP3 inflammasome, and inhibiting Drp1 has been become an attractive therapeutic strategy for inflammatory diseases. This study aimed to investigate the effects of Drp1 inhibitor mdivi‐1 on experimental AD. We firstly detected the effects of mdivi‐1 on primary human keratinocytes in an inflammatory cocktail‐induced AD‐related inflammation in vitro. Results showed that mdivi‐1 inhibited NLRP3 inflammasome activation and pyroptosis which were evidenced by decreased expression of NLRP3, ASC, cleavage of caspase‐1, GSDMD‐NT, mature interleukin (IL)‐1β and IL‐18 in keratinocytes under AD‐like inflammation. Next, mouse model of AD‐like skin lesions was induced by epicutaneous application of 2,4‐dinitrochlorobenzene (DNCB) and mdivi‐1 (25 mg/kg/day, days 5–33 during construction of AD model) was intraperitoneally injected into DNCB‐induced mice. AD mice with mdivi‐1 treatment exhibited ameliorated AD symptoms, lower serum IgE level, and reduced epidermal thickening, mast cells infiltration, and production of IL‐4, IL‐5 and IL‐13 in the lesional tissues. Indeed, mdivi‐1 significantly inhibited NLRP3 inflammasome activation and pyroptotic injury occurred in DNCB‐treated skin tissues. Mechanically, mdivi‐1 regulated the expression of mitochondrial dynamic proteins and suppressed the activation of NF‐κB signal pathway which is an upstream of NLRP3 inflammasome both in vitro and in vivo. This study demonstrated that mdivi‐1 could protect against experimental AD through inhibiting the activation of NLRP3 inflammasome and subsequent inflammatory cytokine release, and mdivi‐1 might exert this function by inhibiting mitochondrial fission and subsequently blocking NF‐κB pathway.

Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Mdivi‐1 alleviates atopic dermatitis through the inhibition of NLRP3 inflammasome

Experimental Dermatology

et al. 2021

“…The mechanism by which DRP1 interacts with Zip1-MCU to allow mitochondrial zinc influx is unclear. Furthermore, whether excess zinc interferes with this mitochondrial surveillance mechanism has not yet been demonstrated in neurons, although it is an intriguing topic of future study due to the extent that DRP1 activation and mitophagy have been implicated in the pathology of various neurodegenerative diseases [ 235 ], such as AD [ 234 , 248 ], PD [ 249 , 250 , 251 ], HD [ 252 , 253 ], ALS [ 254 ], and ischemia [ 255 , 256 ].…”

Section: Zinc and Mitochondrial Dynamicsmentioning

confidence: 99%

The Multifaceted Roles of Zinc in Neuronal Mitochondrial Dysfunction

Gale

Reynolds³

et al. 2021

Biomedicines

Zinc is a highly abundant cation in the brain, essential for cellular functions, including transcription, enzymatic activity, and cell signaling. However, zinc can also trigger injurious cascades in neurons, contributing to the pathology of neurodegenerative diseases. Mitochondria, critical for meeting the high energy demands of the central nervous system (CNS), are a principal target of the deleterious actions of zinc. An increasing body of work suggests that intracellular zinc can, under certain circumstances, contribute to neuronal damage by inhibiting mitochondrial energy processes, including dissipation of the mitochondrial membrane potential (MMP), leading to ATP depletion. Additional consequences of zinc-mediated mitochondrial damage include reactive oxygen species (ROS) generation, mitochondrial permeability transition, and excitotoxic calcium deregulation. Zinc can also induce mitochondrial fission, resulting in mitochondrial fragmentation, as well as inhibition of mitochondrial motility. Here, we review the known mechanisms responsible for the deleterious actions of zinc on the organelle, within the context of neuronal injury associated with neurodegenerative processes. Elucidating the critical contributions of zinc-induced mitochondrial defects to neurotoxicity and neurodegeneration may provide insight into novel therapeutic targets in the clinical setting.

“…The mechanism by which DRP1 interacts with Zip1-MCU to allow mitochondrial zinc influx is unclear. Furthermore, whether excess zinc interferes with this mitochondrial surveillance mechanism has not yet been demonstrated in neurons, although it is an intriguing topic of future study due to the extent that DRP1 activation and mitophagy have been implicated in the pathology of various neurodegenerative diseases [230], such as AD [229,243], PD [244][245][246], HD [247,248], ALS [249], and ischemia [250,251].…”

Section: Fission Fusion and Morphologymentioning

confidence: 99%

The Multifaceted Roles of Zinc in Neuronal Mitochondrial Dysfunction

Gale

Reynolds³

et al. 2021

Preprint

Zinc is a highly abundant cation in the brain, where it is essential for cellular function, including transcription, enzymatic activity, and cell signaling. However, zinc can also trigger injurious cascades in neurons, contributing to the pathology of neurodegenerative diseases. Mitochondria, critical for meeting the high energy demands of the central nervous system (CNS), are a principal target of the deleterious actions of zinc. An increasing body of work suggests that intracellular zinc, can, under certain circumstances, contribute to neuronal damage by inhibiting mitochondrial energy processes, including dissipation of the mitochondrial membrane potential, leading to ATP depletion. Additional consequences of zinc-mediated mitochondrial damage include reactive oxygen species (ROS) generation, mitochondrial permeability transition, and calcium deregulation. Zinc can also induce mitochondrial fission, resulting in mitochondrial fragmentation, as well as inhibition of mitochondrial motility. Here, we review the known mechanisms responsible for the deleterious actions of zinc on the organelle, within the context of neuronal injury associated with neurodegenerative processes. Elucidating the critical contributions of zinc-induced mitochondrial defects to neurotoxicity and neurodegeneration may provide insight into novel therapeutic targets in the clinical setting.