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Porins are beta-barrel proteins translocated to the mitochondrial outer membrane through the TOM complex into the intermembrane space. Porin precursors bind TIM chaperones within the intermembrane space and are guided to the Sorting and Assembly Machinery complex or SAM complex on the outer mitochondrial membrane.
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Nuclear protein sorting regulates nucleus composition and gene expression, crucial for determining the fate of a eukaryotic cell. Hence, the entry and exit of molecules across the nuclear envelope is a tightly controlled process. Nuclear protein sorting can be inhibited by one of the following ways: 1) masking cargo signal sequences, 2) modifying the nuclear receptor's affinity for cargo, 3) controlling the nuclear pore size, 4) retaining the cargo during its transit to the cytosol or the...
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Mitochondrial precursors are translocated to the internal subcompartments via independent mechanisms involving distinct protein machineries called translocases.
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Mitochondria, chloroplasts, and gram-negative bacteria have transmembrane, beta-barrel proteins called porins to mediate the free diffusion of ions and metabolites across the membrane. Mitochondrial porin precursors contain conserved amino acid sequences called beta signals at their C-terminal. Beta signals have a  motif of PoXGXXHyXHy (Po-Polar, X-Any amino acid, G-Glycine, Hy-LargeHydrophobic), which are crucial for precursor recognition to initiate precursor assembly. Beta-barrel...
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Mitochondria are double-membrane organelles of the eukaryotes involved in cellular metabolism, signaling, ATP synthesis, and programmed cell death.  Each of these processes requires specific proteins and enzymes that must be correctly sorted to the right mitochondrial subcompartment for the proper functioning of the organelle.
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A single mitochondrion is a bean-shaped organelle enclosed by a double-membrane system. The outer membrane of mitochondria is smooth and contains many porins - the integral membrane transporters. Porins enable free diffusion of ions and small uncharged molecules through the outer mitochondrial membrane but limit the transport of molecules larger than 5000 Daltons. Further, the outer mitochondrial membrane forms a unique structure called membrane contact sites with other subcellular organelles,...
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Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
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Geranylgeranylated SCFFBXO10 regulates selective outer mitochondrial membrane proteostasis and function.

Sameer Ahmed Bhat1, Zahra Vasi1, Liping Jiang1

  • 1Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, MBRB 1252, Chicago, IL 60607, USA.

Cell Reports
|September 22, 2024
PubMed
Summary

FBXO10 protein targets the outer mitochondrial membrane via geranylgeranylation, regulating mitochondrial function and proteostasis. This mechanism is crucial for cellular health and myogenic differentiation.

Keywords:
CP: MetabolismCP: Molecular biologyE3-ligaseF-box proteinFBXO10HSP90PDE6δmitochondriaprenylationtraffickingubiquitination

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Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Cellular membrane protein turnover, particularly at specific compartments like the outer mitochondrial membrane (OMM), remains poorly understood.
  • The precise mechanisms governing protein localization and function within mitochondria are critical for cellular energy production and homeostasis.

Purpose of the Study:

  • To elucidate the mechanism of FBXO10 targeting to the OMM.
  • To investigate the role of FBXO10 in mitochondrial function and proteostasis.
  • To identify substrates and downstream effects of FBXO10 activity.

Main Methods:

  • Investigated protein lipid modification (geranylgeranylation) of FBXO10 at cysteine 953.
  • Utilized protein interaction studies with cytosolic factors (PDE6δ, HSP90) for OMM targeting.
  • Employed FBXO10 mutants (C953S) to assess mitochondrial function (ATP production, membrane potential, fragmentation).
  • Applied comparative quantitative proteomics to identify mitochondrial substrates.
  • Assessed effects on protein degradation (PGAM5), mitochondrial homeostasis, and myogenic differentiation in iPSCs and myoblasts.

Main Results:

  • FBXO10 undergoes geranylgeranylation at C953, mediating its OMM localization via interaction with PDE6δ and HSP90.
  • The FBXO10(C953S) mutant shows impaired OMM targeting, reduced mitochondrial ATP production, loss of membrane potential, and increased fragmentation.
  • Phosphoglycerate mutase-5 (PGAM5) identified as an OMM-localized substrate of FBXO10.
  • FBXO10 deficiency or a prenylation-deficient mutant inhibits PGAM5 degradation, disrupts mitochondrial homeostasis, and impairs myogenic differentiation.

Conclusions:

  • Geranylgeranylation is a key mechanism for FBXO10 OMM targeting and function.
  • FBXO10 regulates mitochondrial proteostasis through PGAM5 degradation, impacting cellular energy and differentiation.
  • This pathway represents a potential therapeutic target for mitochondrial dysfunction.