Abstract:Mitochondrial fission protein 1 (Fis1) was identified in yeast as being essential for mitochondrial division or fission and subsequently determined to mediate human mitochondrial and peroxisomal fission. Yet, its exact functions in humans, especially in regard to mitochondrial fission, remains an enigma as genetic deletion of Fis1 elongates mitochondria in some cell types, but not others. Fis1 has also been identified as an important component of apoptotic and mitophagic pathways suggesting the protein may hav… Show more
“…Coherently, MFF has been shown to be essential for this oligomerization inhibition at peroxisomes, but not at mitochondria. The involvement of peroxisome specific proteins, such as PEX11 ( Visser et al, 2007 ; Carmichael and Schrader, 2022 ), and other fission machinery proteins, such as FIS1 ( Ihenacho et al, 2021 ), on the vMIA-dependent evasion of antiviral signalling should be adressed in the future, in order to further unravel de mechanisms involved and explain the observed differences between the processes occuring at peroxisomes and mitochondria. Based on all our results, we suggest a model for vMIA’s mechanism of action towards peroxisomes, which is depicted in Figure 6 : upon infection, vMIA interacts with PEX19 at the cytoplasm and travels to peroxisomes, where it interacts with MAVS.…”
Upon intracellular recognition of viral RNA, RIG-I-like proteins interact with MAVS at peroxisomes and mitochondria, inducing its oligomerization and the downstream production of direct antiviral effectors. The human cytomegalovirus (HCMV) is able to specifically evade this antiviral response, via its antiapoptotic protein vMIA. Besides suppressing the programmed cell death of infected cells, vMIA inhibits the antiviral signalling at mitochondria by inducing the organelle’s fragmentation, consequently hindering the interaction between MAVS and the endoplasmic reticulum protein STING. Here we demonstrate that vMIA interferes with the peroxisomal antiviral signalling via a distinct mechanism that is independent of the organelle’s morphology and does not affect STING. vMIA interacts with MAVS at peroxisomes and inhibits its oligomerization, restraining downstream signalling, in an MFF-dependent manner. This study also demonstrates that vMIA is totally dependent on the organelle’s fission machinery to induce peroxisomal fragmentation, while this dependency is not observed at mitochondria. Furthermore, although we demonstrate that vMIA is also able to inhibit MAVS oligomerization at mitochondria, our results indicate that this process, such as the whole vMIA-mediated inhibition of the mitochondrial antiviral response, is independent of MFF. These observed differences in the mechanisms of action of vMIA towards both organelles, likely reflect their intrinsic differences and roles throughout the viral infection. This study uncovers specific molecular mechanisms that may be further explored as targets for antiviral therapy and highlights the relevance of peroxisomes as platforms for antiviral signalling against HCMV.
“…Coherently, MFF has been shown to be essential for this oligomerization inhibition at peroxisomes, but not at mitochondria. The involvement of peroxisome specific proteins, such as PEX11 ( Visser et al, 2007 ; Carmichael and Schrader, 2022 ), and other fission machinery proteins, such as FIS1 ( Ihenacho et al, 2021 ), on the vMIA-dependent evasion of antiviral signalling should be adressed in the future, in order to further unravel de mechanisms involved and explain the observed differences between the processes occuring at peroxisomes and mitochondria. Based on all our results, we suggest a model for vMIA’s mechanism of action towards peroxisomes, which is depicted in Figure 6 : upon infection, vMIA interacts with PEX19 at the cytoplasm and travels to peroxisomes, where it interacts with MAVS.…”
Upon intracellular recognition of viral RNA, RIG-I-like proteins interact with MAVS at peroxisomes and mitochondria, inducing its oligomerization and the downstream production of direct antiviral effectors. The human cytomegalovirus (HCMV) is able to specifically evade this antiviral response, via its antiapoptotic protein vMIA. Besides suppressing the programmed cell death of infected cells, vMIA inhibits the antiviral signalling at mitochondria by inducing the organelle’s fragmentation, consequently hindering the interaction between MAVS and the endoplasmic reticulum protein STING. Here we demonstrate that vMIA interferes with the peroxisomal antiviral signalling via a distinct mechanism that is independent of the organelle’s morphology and does not affect STING. vMIA interacts with MAVS at peroxisomes and inhibits its oligomerization, restraining downstream signalling, in an MFF-dependent manner. This study also demonstrates that vMIA is totally dependent on the organelle’s fission machinery to induce peroxisomal fragmentation, while this dependency is not observed at mitochondria. Furthermore, although we demonstrate that vMIA is also able to inhibit MAVS oligomerization at mitochondria, our results indicate that this process, such as the whole vMIA-mediated inhibition of the mitochondrial antiviral response, is independent of MFF. These observed differences in the mechanisms of action of vMIA towards both organelles, likely reflect their intrinsic differences and roles throughout the viral infection. This study uncovers specific molecular mechanisms that may be further explored as targets for antiviral therapy and highlights the relevance of peroxisomes as platforms for antiviral signalling against HCMV.
“…A 15-kDa soluble domain inside this domain with two tetratricopeptide repeats (TPRs) acts as the tethering site of the mitochondrial outer membrane. The subsequent study found that FS1 recruits DRP1 from the cytosol to the fission site of mitochondria ( Ihenacho et al, 2021 ). Coimmunoprecipitation studies suggest that FIS1 may act as a downstream factor of Mff of DRP1 recruitment and assembly at scission sites ( Shen et al, 2014 ).…”
Section: Significant Players Of Mitochondrial Dynamicsmentioning
Mitochondrial dynamics (fission and fusion) are essential physiological processes for mitochondrial metabolic function, mitochondrial redistribution, and mitochondrial quality control. Various proteins are involved in regulating mitochondrial dynamics. Aberrant expression of these proteins interferes with mitochondrial dynamics and induces a range of diseases. Multiple therapeutic approaches have been developed to treat the related diseases in recent years, but their curative effects are limited. Meanwhile, the role of mitochondrial dynamics in female reproductive function has attracted progressively more attention, including oocyte development and maturation, fertilization, and embryonic development. Here, we reviewed the significance of mitochondrial dynamics, proteins involved in mitochondrial dynamics, and disorders resulting from primary mitochondrial dynamic dysfunction. We summarized the latest therapeutic approaches of hereditary mitochondrial fusion–fission abnormalities and reviewed the recent advances in female reproductive mitochondrial dynamics.
“…After the recruitment to the OMM, Drp1 undergoes GTP-dependent oligomerization forming a spiral ring with an inner diameter of 20 nm [17] (see Table 1). Fis1 Fission Adaptor protein located in the OMM [16] Mdv1 Fission Adaptor protein located in the OMM [16] Mff Fission Adaptor protein located in the OMM [16] dynamin 2 Fission Mediates membrane reorganization [18] endophilin 1 Fission Mediates membrane reorganization [18] SNX9 Fission Mediates membrane reorganization [18] Mfn1-mitofusin1; Mfn2-mitoofusin 2; Opa1-optic atrophy protein 1; Parl-presenilin-associated rhomboidlike protein; Oma1-mitochondrial metalloendopeptidase Oma1; Yme1L1-ATP-dependent zinc metalloprotease YME1 Like 1 ATPase; Afg3l1-mAAA protease complex ATPase family gene-3 yeast-like-1; Drp1dynamin-related protein 1; Fis1-mitochondrial fission protein 1; Mdv1-mitochondrial division protein 1; Mff-mitochondrial fission factor; SNX9-sorting nexin 9; OMM-outer mitochondrial membrane; IMM-inner mitochondrial membrane.…”
Section: Mitochondrial Fissionmentioning
confidence: 99%
“…However, after activation, Drp1 moves from the cytosol to mitochondria [ 15 ]. This translocation is possible due to the activity of adaptor proteins located in the OMMs, such as mitochondrial fission protein 1 (Fis1), mitochondrial division protein 1 (Mdv1), and mitochondrial fission factor (Mff) [ 16 ]. After the recruitment to the OMM, Drp1 undergoes GTP-dependent oligomerization forming a spiral ring with an inner diameter of 20 nm [ 17 ] (see Table 1 ).…”
Cardiovascular disease has been, and remains, one of the leading causes of death in the modern world. The elderly are a particularly vulnerable group. The aging of the body is inevitably accompanied by the aging of all its systems, and the cardiovascular system is no exception. The aging of the cardiovascular system is a significant risk factor for the development of various diseases and pathologies, from atherosclerosis to ischemic stroke. Mitochondria, being the main supplier of energy necessary for the normal functioning of cells, play an important role in the proper functioning of the cardiovascular system. The functioning of each individual cell and the organism as a whole depends on their number, structure, and performance, as well as the correct operation of the system in removing non-functional mitochondria. In this review, we examine the role of mitochondria in the aging of the cardiovascular system, as well as in diseases (for example, atherosclerosis and ischemic stroke). We pay special attention to changes in mitochondrial dynamics since the shift in the balance between fission and fusion is one of the main factors associated with various cardiovascular pathologies.
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