Abstract
The impairment of mitochondrial bioenergetics, often coupled with exaggerated reactive oxygen species (ROS) production, is a fundamental disease mechanism in organs with a high demand for energy, including the heart. Building a more robust and safer cellular powerhouse holds the promise for protecting these organs in stressful conditions. Here, we demonstrate that NADH:ubiquinone oxidoreductase subunit AB1 (NDUFAB1), also known as mitochondrial acyl carrier protein, acts as a powerful cardio-protector by conferring greater capacity and efficiency of mitochondrial energy metabolism. In particular, NDUFAB1 not only serves as a complex I subunit, but also coordinates the assembly of respiratory complexes I, II, and III, and supercomplexes, through regulating iron-sulfur biosynthesis and complex I subunit stability. Cardiac-specific deletion of Ndufab1 in mice caused defective bioenergetics and elevated ROS levels, leading to progressive dilated cardiomyopathy and eventual heart failure and sudden death. Overexpression of Ndufab1 effectively enhanced mitochondrial bioenergetics while limiting ROS production and protected the heart against ischemia-reperfusion injury. Together, our findings identify that NDUFAB1 is a crucial regulator of mitochondrial energy and ROS metabolism through coordinating the assembly of respiratory complexes and supercomplexes, and thus provide a potential therapeutic target for the prevention and treatment of heart failure.
Highlights
Cardiac-specific ablation of NDUFAB1 causes progressive dilated cardiomyopathy leading to heart failure NDUFAB1 was widely expressed in different tissues and was enriched in the heart (Supplementary information, Fig. S1a)
The heart is quite sensitive to mitochondrial dysfunction such that most individuals with mutated mitochondrial proteins eventually develop cardiomyopathy.[5]
Are mitochondria the predominant powerhouses of the heart, supplying more than 90% of the ATP,[2] and excessive mitochondrial reactive oxygen species (ROS) are the culprits in many oxidative heart diseases including IR injury
Summary
The most important player in mitochondrial energy production is the ETC, which consists of four multi-heteromeric complexes (complexes I–IV) in the inner membrane of the organelle They catalyze outward proton movement to build a transmembrane electrochemical gradient that drives ATP synthase (complex V) for ATP synthesis.[8] Individual ETC complexes can organize into supercomplexes (SCs) of different composition and stoichiometry, which have recently been visualized by cryo-electron microscopy.[9,10,11,12,13,14] Such SCs are thought to channel electron transfer more efficiently, limit ROS production, protect vulnerable ETC sites in the complexes from oxidative damage, and stabilize individual complexes.[11,15,16,17,18,19,20,21] Interestingly, SC formation is dynamically regulated in accordance with changes in cellular metabolism,[22,23,24,25] and deficiency of SCs is associated with heart failure.[26] enhancing SC formation might afford an effective therapeutic strategy to make the mitochondria more efficient and safer powerhouses
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