scholarly journals VPS13D bridges the ER to mitochondria and peroxisomes via Miro

2021 ◽  
Vol 220 (5) ◽  
Author(s):  
Andrés Guillén-Samander ◽  
Marianna Leonzino ◽  
Michael G. Hanna ◽  
Ni Tang ◽  
Hongying Shen ◽  
...  
Keyword(s):  
Mitochondrial Membrane ◽  
Secretory Pathway ◽  
Mitochondrial Dynamics ◽  
Transport Proteins ◽  
Lipid Transport ◽  
Outer Mitochondrial Membrane ◽  
Lipid Transfer ◽  
Disease Pathogenesis ◽  
Accessory Factor ◽  
Higher Eukaryotes

Mitochondria, which are excluded from the secretory pathway, depend on lipid transport proteins for their lipid supply from the ER, where most lipids are synthesized. In yeast, the outer mitochondrial membrane GTPase Gem1 is an accessory factor of ERMES, an ER–mitochondria tethering complex that contains lipid transport domains and that functions, partially redundantly with Vps13, in lipid transfer between the two organelles. In metazoa, where VPS13, but not ERMES, is present, the Gem1 orthologue Miro was linked to mitochondrial dynamics but not to lipid transport. Here we show that Miro, including its peroxisome-enriched splice variant, recruits the lipid transport protein VPS13D, which in turn binds the ER in a VAP-dependent way and thus could provide a lipid conduit between the ER and mitochondria. These findings reveal a so far missing link between function(s) of Gem1/Miro in yeast and higher eukaryotes, where Miro is a Parkin substrate, with potential implications for Parkinson’s disease pathogenesis.

scholarly journals Miro recruits VPS13D to mitochondria

2020 ◽  
Author(s):  
Andrés Guillén-Samander ◽  
Marianna Leonzino ◽  
Pietro De Camilli
Keyword(s):  
Secretory Pathway ◽  
Lipid Transfer Protein ◽  
Transport Proteins ◽  
Lipid Transport ◽  
Eukaryotic Cells ◽  
Lipid Transfer ◽  
Transfer Protein ◽  
Accessory Factor ◽  
Mitochondrial Motility ◽  
Higher Eukaryotes

AbstractMitochondria, which are excluded from the secretory pathway, depend on lipid transport proteins for their lipid supply from the ER, where most lipids are synthesized. In yeast, the outer membrane GTPase Gem1 is an accessory factor of ERMES, an ER-mitochondria tethering complex that contains lipid transport domains and plays a function, partially redundant with VPS13, in lipid transfer between the two organelles. In metazoa, where VPS13, but not ERMES, is present, the Gem1 orthologue Miro has been linked to mitochondrial motility but not to lipid transport. Here we show that Miro recruits to mitochondria the lipid transport protein VPS13D which, like Miro, is an essential protein in mammals, and whose localization had remained elusive. We also show that VPS13D can tether mitochondria to the ER in a Miro- and VAP-dependent way. These findings reveal a so far missing link between function(s) of Gem1/Miro in yeast and higher eukaryotes, where Miro is a Parkin substrate, with potential implications for Parkinson’s disease pathogenesis.SummaryProtein-mediated ER-mitochondria lipid transfer is critical for eukaryotic cells. However, the underlying machinery is not well conserved. Guillén-Samander et al, show that Gem1/Miro is an evolutionary conserved link between the yeast ERMES complex and the mammalian lipid transfer protein VPS13D.

scholarly journals Miga-mediated endoplasmic reticulum–mitochondria contact sites regulate neuronal homeostasis

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Lingna Xu ◽  
Xi Wang ◽  
Jia Zhou ◽  
Yunyi Qiu ◽  
Weina Shang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Mammalian Cells ◽  
Mitochondrial Dynamics ◽  
Molecular Organization ◽  
Lipid Transport ◽  
Cellular Processes ◽  
Contact Sites ◽  
Neuronal Homeostasis ◽  
Higher Eukaryotes ◽  
Lateral Sclerosis

Endoplasmic reticulum (ER)–mitochondria contact sites (ERMCSs) are crucial for multiple cellular processes such as calcium signaling, lipid transport, and mitochondrial dynamics. However, the molecular organization, functions, regulation of ERMCS, and the physiological roles of altered ERMCSs are not fully understood in higher eukaryotes. We found that Miga, a mitochondrion located protein, markedly increases ERMCSs and causes severe neurodegeneration upon overexpression in fly eyes. Miga interacts with an ER protein Vap33 through its FFAT-like motif and an amyotrophic lateral sclerosis (ALS) disease related Vap33 mutation considerably reduces its interaction with Miga. Multiple serine residues inside and near the Miga FFAT motif were phosphorylated, which is required for its interaction with Vap33 and Miga-mediated ERMCS formation. The interaction between Vap33 and Miga promoted further phosphorylation of upstream serine/threonine clusters, which fine-tuned Miga activity. Protein kinases CKI and CaMKII contribute to Miga hyperphosphorylation. MIGA2, encoded by the miga mammalian ortholog, has conserved functions in mammalian cells. We propose a model that shows Miga interacts with Vap33 to mediate ERMCSs and excessive ERMCSs lead to neurodegeneration.

scholarly journals Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Majida Charif ◽  
Yvette C. Wong ◽  
Soojin Kim ◽  
Agnès Guichet ◽  
Catherine Vignal ◽  
...  
Keyword(s):  
Optic Neuropathy ◽  
Mitochondrial Membrane ◽  
Ganglion Cells ◽  
Late Onset ◽  
Mitochondrial Dynamics ◽  
Visual Fields ◽  
Adaptor Protein ◽  
Mitochondrial Diseases ◽  
Nerve Degeneration ◽  
Outer Mitochondrial Membrane

AbstractInherited optic neuropathies are the most common mitochondrial diseases, leading to neurodegeneration involving the irreversible loss of retinal ganglion cells, optic nerve degeneration and central visual loss. Importantly, properly regulated mitochondrial dynamics are critical for maintaining cellular homeostasis, and are further regulated by MIEF1 (mitochondrial elongation factor 1) which encodes for MID51 (mitochondrial dynamics protein 51), an outer mitochondrial membrane protein that acts as an adaptor protein to regulate mitochondrial fission. However, dominant mutations in MIEF1 have not been previously linked to any human disease. Using targeted sequencing of genes involved in mitochondrial dynamics, we report the first heterozygous variants in MIEF1 linked to disease, which cause an unusual form of late-onset progressive optic neuropathy characterized by the initial loss of peripheral visual fields. Pathogenic MIEF1 variants linked to optic neuropathy do not disrupt MID51’s localization to the outer mitochondrial membrane or its oligomerization, but rather, significantly disrupt mitochondrial network dynamics compared to wild-type MID51 in high spatial and temporal resolution confocal microscopy live imaging studies. Together, our study identifies dominant MIEF1 mutations as a cause for optic neuropathy and further highlights the important role of properly regulated mitochondrial dynamics in neurodegeneration.

scholarly journals Calcium Deregulation and Mitochondrial Bioenergetics in GDAP1-Related CMT Disease

2019 ◽  
Vol 20 (2) ◽  
pp. 403 ◽  
Author(s):  
Paloma González-Sánchez ◽  
Jorgina Satrústegui ◽  
Francesc Palau ◽  
Araceli del Arco
Keyword(s):  
Mitochondrial Membrane ◽  
Energy Production ◽  
Mitochondrial Dynamics ◽  
Outer Mitochondrial Membrane ◽  
Mitochondrial Network ◽  
Charcot Marie Tooth ◽  
Calcium Deregulation ◽  
Store Operated Calcium Entry ◽  
Mitochondrial Membrane Protein ◽  
Stimulation Of

The pathology of Charcot-Marie-Tooth (CMT), a disease arising from mutations in different genes, has been associated with an impairment of mitochondrial dynamics and axonal biology of mitochondria. Mutations in ganglioside-induced differentiation-associated protein 1 (GDAP1) cause several forms of CMT neuropathy, but the pathogenic mechanisms involved remain unclear. GDAP1 is an outer mitochondrial membrane protein highly expressed in neurons. It has been proposed to play a role in different aspects of mitochondrial physiology, including mitochondrial dynamics, oxidative stress processes, and mitochondrial transport along the axons. Disruption of the mitochondrial network in a neuroblastoma model of GDAP1-related CMT has been shown to decrease Ca2+ entry through the store-operated calcium entry (SOCE), which caused a failure in stimulation of mitochondrial respiration. In this review, we summarize the different functions proposed for GDAP1 and focus on the consequences for Ca2+ homeostasis and mitochondrial energy production linked to CMT disease caused by different GDAP1 mutations.

Glucose metabolism in cancer cells: immunogold localization of hexokinase to the outer mitochondrial membrane

1995 ◽  
Vol 53 ◽  
pp. 1044-1045
Author(s):  
Krishan K. Arora ◽  
Glenn L. Decker ◽  
Peter L. Pedersen
Keyword(s):  
Tumor Cells ◽  
Mitochondrial Membrane ◽  
Present Report ◽  
Large Fraction ◽  
Mitochondrial Fraction ◽  
Immunogold Labeling ◽  
Outer Mitochondrial Membrane ◽  
Immunogold Localization ◽  
Hexokinase Activity ◽  
Normal Tissues

Hexokinase (ATP: D-hexose 6-phophotransferase EC 2.7.1.1) is the first enzyme of the glycolytic pathway which commits glucose to catabolism by catalyzing the phosphorylation of glucose with ATP. Previous studies have shown diat hexokinase activity is markedly elevated in rapidly growing tumor cells exhibiting high glucose catabolic rates. A large fraction (50-80%) of this enzyme activity is bound to the mitochondrial fraction (1,2) where it has preferred access to ATP (3). In contrast,the hexokinase activity of normal tissues is quite low, with one exception being brain which is a glucose-utilizing tissue (4). Biochemical evidence involving rigorous subfractionation studies have revealed striking differences between the subcellular distribution of hexokinase in normal and tumor cells [See review by Arora et al (4)].In the present report, we have utilized immunogold labeling techniques to evaluate die subcellular localization of hexokinase in highly glycolytic AS-30D hepatoma cells and in the tissue of its origin, i.e., rat liver.

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