A salvage pathway maintains highly functional respiratory complex I

Abstract

Regulation of the turnover of complex I (CI), the largest mitochondrial respiratory chain complex, remains enigmatic despite huge advancement in understanding its structure and the assembly. Here, we report that the NADH-oxidizing N-module of CI is turned over at a higher rate and largely independently of the rest of the complex by mitochondrial matrix protease ClpXP, which selectively removes and degrades damaged subunits. The observed mechanism seems to be a safeguard against the accumulation of dysfunctional CI arising from the inactivation of the N-module subunits due to attrition caused by its constant activity under physiological conditions. This CI salvage pathway maintains highly functional CI through a favorable mechanism that demands much lower energetic cost than de novo synthesis and reassembly of the entire CI. Our results also identify ClpXP activity as an unforeseen target for therapeutic interventions in the large group of mitochondrial diseases characterized by the CI instability.

Energy deficit-independent stress response in the Frataxin-depleted heart: evidence that Integrated Stress Response can predominate over mTORC1 activation

“…Our observations indicate preserved Complex III but lower Complex I activity. Possibly, protein half-life is prolonged when proteins are assembled into a complex, and more so for Complex III than for Complex I whose N module, which protrudes into the matrix, is susceptible to greater turnover (Szczepanowska, Senft et al, 2020). Yet, differential protein degradation might not fully explain our findings because protein levels of SDHB and Complex II in-gel activity, though decreased, were higher than might be expected given the relatively short half-life of Complex II subunits (Fornasiero et al, 2018).…”

Mitochondrial CLPP2 Assists Coordination and Homeostasis of Respiratory Complexes

“…In CLPP-deficient mice, reduced protein levels in complex I subunits have also been observed (Deepa et al, 2016;Szczepanowska et al, 2016). Recently, it was discovered that turnover of the N-module within BN-PAGE-purified intact mitochondrial complexes was faster in proliferating than in differentiated mammalian cell cultures (Szczepanowska et al, 2020). It was proposed that ClpXP protease plays a key role in complex I maintenance, acting through surveillance and replacement of expended N-modules (Szczepanowska et al, 2020).…”

“…Recently, it was discovered that turnover of the N-module within BN-PAGE-purified intact mitochondrial complexes was faster in proliferating than in differentiated mammalian cell cultures (Szczepanowska et al, 2020). It was proposed that ClpXP protease plays a key role in complex I maintenance, acting through surveillance and replacement of expended N-modules (Szczepanowska et al, 2020). It was shown that to regenerate stalled complex I, ClpXP can recognize, disassemble, and rapidly degrade impaired N-module proteins, allowing an effective replacement of N-module components in preexisting complex I (Szczepanowska et al, 2020).…”

“…It was proposed that ClpXP protease plays a key role in complex I maintenance, acting through surveillance and replacement of expended N-modules (Szczepanowska et al, 2020). It was shown that to regenerate stalled complex I, ClpXP can recognize, disassemble, and rapidly degrade impaired N-module proteins, allowing an effective replacement of N-module components in preexisting complex I (Szczepanowska et al, 2020). In plants, it is still not clear how dysfunction of CLPP2 impairs the incorporation of complex I subunits into complex I and supercomplex I1III 2 based on in vitro import analyses ( Fig.…”

Bi‐allelic pathogenic variants in NDUFC2 cause early‐onset Leigh syndrome and stalled biogenesis of complex I

“…Moreover, it indicates an important role for NDUFC2 in the assembly of the membrane arm of complex I, particularly involving the ND2 module and, possibly, the ND1 module. Complexome profiling of complex I‐deficient subject cell lines continues to be a useful tool in elucidating the molecular mechanisms underlying complex I assembly and stability (Szczepanowska et al , 2020).…”