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Last update 08 May 2025

FIS1

Last update 08 May 2025

Basic Info

Synonyms

CGI-135, FIS1, FIS1 homolog

+ [7]

Introduction

Involved in the fragmentation of the mitochondrial network and its perinuclear clustering (PubMed:12783892, PubMed:12861026, PubMed:14996942, PubMed:23283981). Plays a minor role in the recruitment and association of the fission mediator dynamin-related protein 1 (DNM1L) to the mitochondrial surface and mitochondrial fission (PubMed:12861026, PubMed:16118244, PubMed:23283981, PubMed:23530241, PubMed:24196833). May not be essential for the assembly of functional fission complexes and the subsequent membrane scission event (PubMed:23530241, PubMed:24196833). Also mediates peroxisomal fission (PubMed:16107562). May act when the products of fission are directed toward mitochondrial homeostasis, mitophagy, or apoptosis (PubMed:24196833). Can induce cytochrome c release from the mitochondrion to the cytosol, ultimately leading to apoptosis (PubMed:12783892).

Drugs associated with 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 FIS1

100 Translational Medicine associated with FIS1

0 Patents (Medical) associated with FIS1

947

Literatures (Medical) associated with FIS1

31 Dec 2025·Pharmaceutical Biology

Harmine derivative H-2-168 induces the death of Echinococcus granulosus by regulating mitochondrial fusion and fission

Article

Author: Wang, Jianhua ; Pan, Meichi ; Gong, Yuehong ; Zhao, Meiling ; Zhao, Yicong ; Liu, Junpeng ; Wen, Hao

CONTEXTH-2-168 has pharmacological effects similar to those of harmine, with less toxicity. The health of cells and organisms depends on a delicate balance between mitochondrial fusion and fission.OBJECTIVEThis study investigated the roles of H-2-168 and mitochondrial fusion and fission in Echinococcus granulosus.MATERIALS AND METHODSNotably, E. granulosus were isolated from fresh sheep livers, and then treated with H-2-168 (25 μg/mL), mitochondrial division inhibitor 1 (Mdivi-1, 25 μg/mL) or the combination of H-2-168:Mdivi-1 (25 μg/mL:12.5 μg/mL). After 24 h of culture, the indices related to E. granulosus were measured. Additionally, Drp1 was knocked down to explore its effects on E. granulosus growth.RESULTSThe EC₅₀ values of H-2-168, Mdivi-1 and H-2-168:Mdivi-1 against E. granulosus were 44.171, 117.882 and 32.924 μg/mL, respectively. Compared with H-2-168 or Mdivi-1, the combination of H-2-168 and Mdivi-1 showed better inhibitory effects on E. granulosus viability, as well as increased levels of ROS and LDH, decreased ATP levels, inhibited mitochondrial activity and reduced mitochondrial membrane potential (p < 0.05), with the upregulation of Caspase-3, Cyt-c, Drp1, Fis1 and downregulation of Bcl-2, Mfn2 and OPA1. Additionally, Drp1 knockdown was successfully performed in E. granulosus, which significantly inhibited E. granulosus viability (p < 0.05) and further downregulated Mfn2 expression induced by H-2-168.DISCUSSION AND CONCLUSIONDrp1 is closely associated with mitochondrial fusion and fission, and H-2-168 may promote E. granulosus death through disrupting the balance between mitochondrial fusion and fission.

01 Aug 2025·Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

Consecutive skeletal muscle PGC-1α overexpression: A double-edged sword for mitochondrial health in the aging brain

Article

Author: Koltai, Erika ; Radák, Zsolt ; Kolonics, Attila ; Giannopoulou, Smaragda ; Mozaffaritabar, Soroosh ; Gu, Yaodong ; Zhou, Lei ; Pinho, Ricardo A ; Boldogh, Istvan ; Miklossy, Ildiko

Mitochondrial dysfunction is a critical contributor to age-related functional declines in skeletal muscle and brain. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is essential for mitochondrial biogenesis and function during aging. While skeletal muscle-specific overexpression of PGC-1α is known to mimic exercise-induced benefits in young animals, its chronic systemic effects on aging tissues remain unclear. This study aimed to determine the lifelong impact of skeletal muscle-specific PGC-1α overexpression on mitochondrial health, oxidative stress, inflammation, and cognitive function in aged mice. We established three experimental groups: young wild-type mice (3-4 months old), aged wild-type mice (25-27 months old), and aged mice with skeletal muscle-specific PGC-1α overexpression (24-27 months old). In skeletal muscle, aging led to significant reductions in mitochondrial biogenesis markers, including PGC-1α, FNDC5, and mtDNA content. PGC-1α overexpression reversed this decline, elevating the expression of PGC-1α, SIRT1, LONP1, SDHA, CS, TFAM, eNOS, and mtDNA levels, suggesting preserved mitochondrial biogenesis. However, FNDC5 and SIRT3 were paradoxically suppressed, indicating potential compensatory feedback mechanisms. PGC-1α overexpression also enhanced anabolic signaling, as evidenced by increased phosphorylation of mTOR and S6, and reduced FOXO1 expression, favoring a muscle growth-promoting environment. Moreover, aging impaired mitochondrial dynamics by downregulating MFN1, MFN2, OPA1, FIS1, and PINK1. While PGC-1α overexpression did not restore fusion-related proteins, it further reduced fission-related protein and enhanced mitophagy proteins, as evidenced by increased PINK1 phosphorylation. In contrast, in the hippocampus, muscle-specific PGC-1α overexpression exacerbated age-associated mitochondrial biogenesis decline. Expression levels of key mitochondrial markers, including PGC-1α, SIRT1, CS, FNDC5, Cytochrome C, and TFAM, were further reduced compared to aged wild-type controls. mTOR phosphorylation was also significantly suppressed, whereas cognition-related proteins (BDNF, VEGF, eNOS) and performance in behavioral tests remained unchanged. Importantly, skeletal muscle-specific PGC-1α overexpression triggered pronounced oxidative stress and inflammatory responses in both skeletal muscle and the hippocampus. In skeletal muscle, elevated levels of protein carbonyls, IκB-α, NF-κB, TNF-α, SOD2, and NRF2 were observed, accompanied by a reduction in the DNA repair enzyme OGG1. Notably, similar patterns were detected in the hippocampus, including increased expression of protein carbonyls, iNOS, NF-κB, TNF-α, SOD2, GPX1, and NRF2, alongside decreased OGG1 levels. These findings suggest that the overexpression of PGC-1α in skeletal muscle may have contributed to systemic oxidative stress and inflammation. In conclusion, skeletal muscle-specific PGC-1α overexpression preserves mitochondrial biogenesis and enhances anabolic signaling in aging muscle but concurrently induces oxidative stress and inflammatory responses, which may adversely affect mitochondrial health in the brain. These results emphasize the complex role of the skeletal muscle PGC-1α during aging.

01 Jun 2025·Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

HUWE1-mediated ubiquitination and degradation of oxidative damage repair gene ATM maintains mitochondrial quality control system in lens epithelial cells

Article

Author: Zhang, Guowei ; Guan, Huaijin ; Bao, Sijie ; Shi, Haihong ; Li, Pengfei ; Wang, Congyu ; Wang, Siwen ; Ji, Min ; Kang, Lihua

Mitochondrial dysfunction, resulting from a diminished oxidative damage repair capacity of mitochondrial DNA (mtDNA) in peripheral lens epithelial cells (LECs), is a key pathogenic mechanism in age-related cortical cataract (ARCC). This study aims to investigate the potential role of the E3 ligase HUWE1 and its ubiquitination substrate, the oxidative damage repair gene ATM, in the pathogenesis of ARCC. Our findings reveal that ATM protein expression is downregulated in human peripheral lens epithelial cells and the turbid cortex, correlating with increased expression of HUWE1. Overexpression of ATM is shown to repair damaged mtDNA, protect mitochondria in LECs from oxidative damage, inhibit mitochondrial fission, enhance mitochondrial biogenesis and mitophagy, and prevent LECs apoptosis. Conversely, overexpression of HUWE1 may negate the protective effects of ATM via the ubiquitination pathway, promote oxidative stress-induced mitochondrial damage, increase the expression of mitochondrial fission proteins Drp1/Fis1, lead to mitochondrial network fragmentation and LECs apoptosis. In a SD rat lens model ex vitro, the ATM inhibitor AZD0156 exacerbated lens opacity, whereas the mitochondrial fission inhibitor Mdivi-1 restored lens transparency. These results suggest that modulating key molecules involved in oxidative damage repair and mitochondrial fission pathways could enhance mitochondrial quality control, paving the way for the development of targeted molecular therapies for the prevention and treatment of ARCC.

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FIS1

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