Geranylgeranylated-SCF^FBXO10 Regulates Selective Outer Mitochondrial Membrane Proteostasis and Function.

Area of Science:

• Cell Biology
• Biochemistry
• Molecular Biology

Background:

• E3-ubiquitin ligases (E3s) regulate protein homeostasis via the ubiquitin-proteasome system (UPS).
• Mechanisms controlling E3 ligase localization and substrate specificity at organelle membranes, like the outer mitochondrial membrane (OMM), remain unclear.
• Understanding these processes is crucial for cellular health and disease.

Approach:

• Investigated the role of FBXO10, an SCF-E3 ligase component, in mitochondrial protein regulation.
• Utilized geranylgeranylation modification at Cysteine953 (C953) to study FBXO10 trafficking to the OMM.
• Employed mass spectrometry to identify OMM substrates and assessed mitochondrial function and myogenic differentiation in FBXO10 mutants.

Key Points:

• FBXO10 undergoes geranylgeranylation at C953, directing it to the OMM via interactions with PDE6δ and HSP90.
• Geranylgeranylation-deficient FBXO10(C953S) impairs mitochondrial ATP production, membrane potential, and increases fragmentation.
• FBXO10 targets Phosphoglycerate mutase 5 (PGAM5) for ubiquitination and degradation at the OMM.

Conclusions:

• FBXO10-mediated PGAM5 degradation is essential for maintaining mitochondrial homeostasis and myogenic differentiation.
• This study reveals a novel mechanism for E3 ligase-driven regulation of mitochondrial membrane proteostasis and metabolic health.
• The findings suggest potential therapeutic strategies targeting mitochondrial function.