Human Fis1 directly interacts with Drp1 in an evolutionarily conserved manner to promote mitochondrial fission

Nolden, Kelsey A.; Harwig, Megan C.; Hill, R. Blake

doi:10.1016/j.jbc.2023.105380

Cited by 7 publications

(3 citation statements)

References 91 publications

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“…Consistent with these results, OPA1, a major determinant of mitochondria cristae morphology and remodeling and inner mitochondrial membrane fusion, 35–37 was selectively downregulated in ORF3a‐A549 cells, as determined by RNA‐seq (Figure 3B) and qRT‐PCR (Figure 4J). Intriguingly, FIS1, a promoter of mitochondrial fission, 38–40 was also downregulated in ORF3a‐A549 cells (Figure 4K), in spite of the observed enhanced mitochondrial fission. In this regard, although FIS1 is a major recruiter of DRP1 to the mitochondrial outer membrane to execute fission, its silencing does not elongate mitochondria in all cell types 41,42 and human DRP1 can be recruited by other mitochondrial membrane–anchored proteins, particularly MFF, 41,43–48 and, as such, downregulation of FIS1 in our system does not necessarily counter our morphological observations.…”

Section: Resultsmentioning

confidence: 91%

Metabolic and mitochondria alterations induced by SARS‐CoV‐2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10

López‐Ayllón,

Marin,

Fernández

et al. 2024

Journal of Medical Virology

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Antiviral signaling, immune response and cell metabolism are dysregulated by SARS‐CoV‐2, the causative agent of COVID‐19. Here, we show that SARS‐CoV‐2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10 induce a significant mitochondrial and metabolic reprogramming in A549 lung epithelial cells. While ORF9b, ORF9c and ORF10 induced largely overlapping transcriptomes, ORF3a induced a distinct transcriptome, including the downregulation of numerous genes with critical roles in mitochondrial function and morphology. On the other hand, all four ORFs altered mitochondrial dynamics and function, but only ORF3a and ORF9c induced a marked alteration in mitochondrial cristae structure. Genome‐Scale Metabolic Models identified both metabolic flux reprogramming features both shared across all accessory proteins and specific for each accessory protein. Notably, a downregulated amino acid metabolism was observed in ORF9b, ORF9c and ORF10, while an upregulated lipid metabolism was distinctly induced by ORF3a. These findings reveal metabolic dependencies and vulnerabilities prompted by SARS‐CoV‐2 accessory proteins that may be exploited to identify new targets for intervention.

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Section: Resultsmentioning

confidence: 91%

Metabolic and mitochondria alterations induced by SARS‐CoV‐2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10

López‐Ayllón,

Marin,

Fernández

et al. 2024

Journal of Medical Virology

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“…It is also worth mentioning that the presence of Fis1 effects that are unrelated to its direct interaction with DRP1 and characterized by its ability to block mitochondrial fusion by inhibiting the GTPase activity of the fusion proteins Mfn1, Mfn2, and OPA1 casts doubt on viewing Fis1 as a DRP1 receptor [25]. However, a recent study [26] showed a direct interaction between Fis1 and DRP1, and the authors considered Fis1 as a switch from homeostatic to mitophagic division.…”

Section: Role Of Drp1 In the Regulation Of Mitochondrial Dynamicsmentioning

confidence: 99%

DRP1 Regulation as a Potential Target in Hypoxia-Induced Cerebral Pathology

Fedorova,

Egorova,

Voronkov

et al. 2023

JMP

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The following review considers current concepts concerning the characteristics of DRP1-related mitochondrial division in brain cells during hypoxic-ischemic pathology. The functional role of DRP1 in neurons and astroglia in cerebral ischemia conditions was analyzed. We discuss the potential for regulating DRP1 activity through the selective inhibitor of mitochondrial fission, mdivi-1. The article also presents data on DRP1 involvement in astro- and microglia-mediated intercellular mitochondrial transport. Understanding of the molecular mechanisms responsible for mitochondrial fission during hypoxic-ischemic exposure will allow us to consider DRP1 as an effective therapeutic target for treating conditions with a hypoxic component.

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“…Studies have demonstrated notable reductions in the levels of Mfn1/2 and Opa1 in various pathological processes [ 10 ]. Conversely, pathological conditions elicit an elevation in the expression levels of fission proteins Drp1 and Fis1 [ 11 , 12 ]. Therefore, targeting the modulation of mitochondrial kinetic homeostasis and reduction of reactive oxygen species production holds promise as potential therapeutic approaches in the development of new strategies against renal fibrosis.…”

Section: Introductionmentioning

confidence: 99%

Combined use of Panax notoginseng and leech provides new insights into renal fibrosis: Restoration of mitochondrial kinetic imbalance

Chen,

Deng,

Zuo

et al. 2024

PLoS ONE

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In this study, we aimed to investigate the protective effects of Panax notoginseng and leech (PL) on renal fibrosis and explore the mechanisms underlying their actions. For this study, we created an adenine-induced renal fibrosis model in SD rats to investigate the protective effect of PL on renal fibrosis and explore its underlying mechanism. Initially, we assessed the renal function in RF rats and found that Scr, BUN, and urine protein content decreased after PL treatment, indicating the protective effect of PL on renal function. Histological analysis using HE and Masson staining revealed that PL reduced inflammatory cell infiltration and decreased collagen fiber deposition in renal tissue. Subsequently, we analyzed the levels of α-SMA, Col-IV, and FN, which are the main components of the extracellular matrix (ECM), using IHC, RT-qPCR, and WB. The results demonstrated that PL was effective in reducing the accumulation of ECM, with PL1-2 showing the highest effectiveness. To further understand the underlying mechanisms, we conducted UPLC-MS/MS analysis on the incoming components of the PL1-2 group. The results revealed several associations between the differential components and antioxidant and mitochondrial functions. This was further confirmed by enzyme-linked immunosorbent assay and biochemical indexes, which showed that PL1-2 ameliorated oxidative stress by reducing ROS and MDA production and increasing GSH and SOD levels. Additionally, transmission electron microscopy results indicated that PL1-2 promoted partial recovery of mitochondrial morphology and cristae. Finally, using RT-qPCR and WB, an increase in the expression of mitochondrial fusion proteins Mfn1, Mfn2, and Opa1 after PL1-2 treatment was observed, coupled with a decline in the expression and phosphorylation of mitochondrial cleavage proteins Fis and Drp1. These findings collectively demonstrate that PL1-2 ameliorates renal fibrosis by reducing oxidative stress and restoring mitochondrial balance.

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Human Fis1 directly interacts with Drp1 in an evolutionarily conserved manner to promote mitochondrial fission

Cited by 7 publications

References 91 publications

Metabolic and mitochondria alterations induced by SARS‐CoV‐2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10

Metabolic and mitochondria alterations induced by SARS‐CoV‐2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10

DRP1 Regulation as a Potential Target in Hypoxia-Induced Cerebral Pathology

Combined use of Panax notoginseng and leech provides new insights into renal fibrosis: Restoration of mitochondrial kinetic imbalance

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