Formation of I₂+III₂ supercomplex rescues respiratory chain defects.

Area of Science:

• Mitochondrial biology
• Structural biology
• Biochemistry

Background:

• Mitochondrial electron transport chain (ETC) complexes exist as free units or supercomplexes (SCs).
• The physiological roles and formation mechanisms of SCs are not fully understood.
• The function of Complex III (CIII) and its assembly into SCs are critical for cellular respiration.

Purpose of the Study:

• To investigate the formation and function of a specialized extra-large supercomplex (SC-XL) in response to CIII perturbations.
• To elucidate the structural basis and physiological impact of SC-XL formation.
• To explore the therapeutic potential of manipulating SC-XL formation in mitochondrial dysfunction.

Main Methods:

• Cryoelectron microscopy (cryo-EM) to resolve the structure of SC-XL.
• Genetic manipulation of CIII biogenesis in mammalian cells.
• Assessment of mitochondrial respiration, reactive oxygen species (ROS) production, and fatty acid oxidation (FAO).
• Inhibition of SC-XL formation using specific mutations.
• Studies in mouse models of ischemic heart failure.

Main Results:

• Genetic perturbations in CIII biogenesis stimulate the formation of an I₂+III₂ SC-XL.
• SC-XL formation increases mitochondrial cristae density, reduces CIII-derived ROS, and sustains respiration despite significant CIII deficiency.
• Inhibiting SC-XL formation exacerbates respiratory problems in CIII mutants.
• SC-XL formation promotes FAO and confers protection against ischemic heart failure in mice.

Conclusions:

• Mammalian ETC exhibits plasticity, with structural adaptations like SC-XL formation mitigating intrinsic perturbations.
• SC-XL formation is a crucial compensatory mechanism for CIII deficiency, impacting cellular respiration and organ protection.
• Targeting SC-XL formation represents a potential therapeutic strategy for treating mitochondrial dysfunction and related diseases.