Last update 01 Nov 2024

DNM1L x FIS1

Last update 01 Nov 2024

Basic Info

Related Targets

DNM1LFIS1

Drugs associated with DNM1L x FIS1

P-110 (Stanford University)

Target

DNM1L x FIS1

Mechanism

DNM1L inhibitors [+1]

Active Org.

Case Western Reserve University School of Medicine

Originator Org.

Stanford University

Active Indication

Parkinson Disease

Inactive Indication

Alzheimer Disease [+1]

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with DNM1L x FIS1

100 Translational Medicine associated with DNM1L x FIS1

0 Patents (Medical) associated with DNM1L x FIS1

172

Literatures (Medical) associated with DNM1L x FIS1

01 Nov 2024·Experimental Gerontology

The mitochondrial function of peripheral blood mononuclear cells in frail older patients

Article

Author: Ding, Guoxian ; Huang, Tingting ; Zhang, Danmei ; Tong, Qiangwei ; Qin, Li ; Zhu, Qianqian ; Liu, Juan

BACKGROUNDFrailty increases the incidence of geriatric syndromes and even the risk of death in old adults. However, the diagnostic criteria for frailty are inconsistent because of complex pathological processes and diverse clinical manifestations. To determine the effective biomarker and recognize frail status early, we investigated the correlation of mitochondrial morphology and function of human peripheral blood mononuclear cells (PBMCs) with frailty status in older adults.METHODSThis Cross-sectional study followed 393 participants (aged 25-100 years, female 31.04 %) from the First Affiliated Hospital of Nanjing Medical University. The frailty status of subjects was assessed by the physical frailty phenotype (PFP) scale. We analyzed mitochondria functions including mitochondria copy number (mtDNAcn), the mRNA expressions of mitochondrial dynamics-related genes mitofusin 1(MFN1), mitofusin 2(MFN2), optic atrophy protein-1(OPA1), fission protein-1(FIS1) and dynamin-related protein 1(DRP1), mitochondrial oxidative respiration and reactive oxygen species(ROS) levels in PBMCs. Mitochondria morphology, size, and number were observed by transmission electron microscopy (TEM).RESULTSAfter adjustment for sex and BMI, mtDNAcn, the mRNA expression of FIS1, mitochondrial respiratory function (proton leak, maximum oxygen consumption, and respiratory reserve) and ROS level were significantly correlated with age (P = 0.031, 0.030, 0.042, 0.003, 0.002, 0.022, respectively). After correcting for age, sex, and BMI, mtDNAcn and the mRNA expression of OPA1 were correlated with 4 m gait speed respectively (P = 0.003, 0.028, respectively). Compared with non-frail people, mtDNAcn, the mRNA expression of MFN1, mitochondrial basal respiration, proton leak, maximum oxygen consumption, ATP production and space capacity were significantly decreased in frail older adults (P = 0.013, 0.036, 0.026, 0.024, 0.012, 0.032, 0.020, respectively). ROS levels were significantly increased in the frail group (P = 0.016). Compared with non-frail people, the number, length, and perimeter, area of mitochondria were reduced in frail group under TEM (all P < 0.001).CONCLUSIONMitochondrial dysfunctions (decreased mtDNAcn, impaired mitochondrial morphology, imbalanced mitochondrial dynamic, impaired mitochondrial respiratory function, and increased ROS levels) were significantly correlated with frail status.

01 Oct 2024·Apoptosis

SIRT1 regulates mitochondrial fission to alleviate high altitude hypoxia inducedcardiac dysfunction in rats via the PGC-1α-DRP1/FIS1/MFF pathway

Article

Author: Zhang, Ling ; Wang, Zirou ; Zhang, Xiaoru ; Xu, Hongbao ; Pu, Lingling ; Wang, Xinxing ; Ai, Chongyi ; Wang, Guangrui ; Li, Ran ; Liu, Weili ; Chen, Zhaoli ; Cheng, Xiaoling ; Song, Xiaona

High-altitude exposure has been linked to cardiac dysfunction. Silent information regulator factor 2-related enzyme 1 (sirtuin 1, SIRT1), a nicotinamide adenine dinucleotide-dependent deacetylase, plays a crucial role in regulating numerous cardiovascular diseases. However, the relationship between SIRT1 and cardiac dysfunction induced by hypobaric hypoxia (HH) remains unexplored. This study aims to assess the impact of SIRT1 on HH-induced cardiac dysfunction and delve into the underlying mechanisms, both in vivo and in vitro. In this study, we have demonstrated that exposure to HH results in cardiomyocyte injury, along with the downregulation of SIRT1 and mitochondrial dysfunction. Upregulating SIRT1 significantly inhibits mitochondrial fission, improves mitochondrial function, reduces cardiomyocyte injury, and consequently enhances cardiac function in HH-exposed rats. Additionally, HH exposure triggers aberrant expression of mitochondrial fission-regulated proteins, with a decrease in PPARγ coactivator 1 alpha (PGC-1α) and mitochondrial fission factor (MFF) and an increase in mitochondrial fission 1 (FIS1) and dynamin-related protein 1 (DRP1), all of which are mitigated by SIRT1 upregulation. Furthermore, inhibiting PGC-1α diminishes the positive effects of SIRT1 regulation on the expression of DRP1, MFF, and FIS1, as well as mitochondrial fission. These findings demonstrate that SIRT1 alleviates HHinduced cardiac dysfunction by preventing mitochondrial fission through the PGC-1α-DRP1/FIS1/MFF pathway.

01 Sep 2024·Cell Reports Medicine

Acutely blocking excessive mitochondrial fission prevents chronic neurodegeneration after traumatic brain injury

Article

Author: Sridharan, Preethy S ; Cintrón-Pérez, Coral J. ; Barker, Sarah ; Liu, Hui ; Kang, David E ; Woo, Jung-A A ; Cheng, Feixiong ; Wilson, Brigid M ; Gefen, Tamar ; Kang, David E. ; Hu, Di ; Chaubey, Kalyani ; Kee, Teresa R ; Vázquez-Rosa, Edwin ; Bykova, Marina ; Castellani, Rudolph J. ; Pieper, Andrew A ; Miller, Emiko ; Fujioka, Hisashi ; Koh, Yeojung ; Woo, Jung-A.A. ; Paul, Bindu D ; Shin, Min-Kyoo ; Chakraborty, Suwarna ; Cintrón-Pérez, Coral J ; Paul, Bindu D. ; León-Alvarado, Rose A ; León-Alvarado, Rose A. ; Franke, Kathryn ; Sridharan, Preethy S. ; Qi, Xin ; Castellani, Rudolph J ; Flanagan, Margaret E. ; Pieper, Andrew A. ; Flanagan, Margaret E ; Kee, Teresa R. ; Dou, Lijun ; Dhar, Matasha ; Wilson, Brigid M. ; Tripathi, Sunil Jamuna

Progression of acute traumatic brain injury (TBI) into chronic neurodegeneration is a major health problem with no protective treatments. Here, we report that acutely elevated mitochondrial fission after TBI in mice triggers chronic neurodegeneration persisting 17 months later, equivalent to many human decades. We show that increased mitochondrial fission after mouse TBI is related to increased brain levels of mitochondrial fission 1 protein (Fis1) and that brain Fis1 is also elevated in human TBI. Pharmacologically preventing Fis1 from binding its mitochondrial partner, dynamin-related protein 1 (Drp1), for 2 weeks after TBI normalizes the balance of mitochondrial fission/fusion and prevents chronically impaired mitochondrial bioenergetics, oxidative damage, microglial activation and lipid droplet formation, blood-brain barrier deterioration, neurodegeneration, and cognitive impairment. Delaying treatment until 8 months after TBI offers no protection. Thus, time-sensitive inhibition of acutely elevated mitochondrial fission may represent a strategy to protect human TBI patients from chronic neurodegeneration.

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