CLPB disaggregase dysfunction impacts the functional integrity of the proteolytic SPY complex

Area of Science:

• Mitochondrial biology
• Molecular genetics
• Cellular quality control

Background:

• CLPB (Caseinolytic peptidase B) is a mitochondrial AAA+ disaggregase.
• Mutations in CLPB cause 3-methylglutaconic aciduria and neutropenia, but the underlying molecular mechanisms are unclear.
• CLPB interacts with mitochondrial quality control (QC) factors, suggesting a role in organelle homeostasis.

Purpose of the Study:

• To define the CLPB substrate profile and understand its role in mitochondrial QC.
• To investigate the molecular mechanism linking CLPB deficiency to disease pathology.
• To elucidate the interplay between CLPB and other mitochondrial QC proteins.

Main Methods:

• Proteomic analysis to identify CLPB substrates.
• Biochemical assays to assess protein aggregation and mitochondrial function.
• Studies in a CLPB-null environment to observe stress-specific phenotypes.

Main Results:

• CLPB deficiency leads to stress-specific protein aggregation in the mitochondrial intermembrane space.
• The CLPB substrate profile was defined, revealing its role in managing protein homeostasis.
• CLPB deficiency impairs the function of the SPY complex (STOML2, PARL, YME1L1) via intermembrane space aggregation.

Conclusions:

• Mitochondrial QC components at the intermembrane space/inner membrane interface are interdependent.
• CLPB is crucial for maintaining the function of the SPY complex.
• Dysregulation of this mitochondrial QC network underlies CLPB-related disease pathology.