Abstract

Cardiolipin (CL) is a signature phospholipid of the mitochondria required for the formation of mitochondrial respiratory chain (MRC) supercomplexes. The destabilization of MRC supercomplexes is the proximal cause of the pathology associated with the depletion of CL in patients with Barth syndrome. Thus, promoting supercomplex formation could ameliorate mitochondrial dysfunction associated with CL depletion. However, to date, physiologically relevant small-molecule regulators of supercomplex formation have not been identified. Here, we report that ethanolamine (Etn) supplementation rescues the MRC defects by promoting supercomplex assembly in a yeast model of Barth syndrome. We discovered this novel role of Etn while testing the hypothesis that elevating mitochondrial phosphatidylethanolamine (PE), a phospholipid suggested to overlap in function with CL, could compensate for CL deficiency. We found that the Etn supplementation rescues the respiratory growth of CL-deficient Saccharomyces cerevisiae cells in a dose-dependent manner but independently of its incorporation into PE. The rescue was specifically dependent on Etn but not choline or serine, the other phospholipid precursors. Etn improved mitochondrial function by restoring the expression of MRC proteins and promoting supercomplex assembly in CL-deficient cells. Consistent with this mechanism, overexpression of Cox4, the MRC complex IV subunit, was sufficient to promote supercomplex formation in CL-deficient cells. Taken together, our work identifies a novel role of a ubiquitous metabolite, Etn, in attenuating mitochondrial dysfunction caused by CL deficiency.

Highlights

  • Cardiolipin (CL) is a signature phospholipid of the mitochondria required for the formation of mitochondrial respiratory chain (MRC) supercomplexes

  • We discovered this novel role of Etn while testing the hypothesis that elevating mitochondrial phosphatidylethanolamine (PE), a phospholipid suggested to overlap in function with CL, could compensate for CL deficiency

  • Our work identifies a novel role of a ubiquitous metabolite, Etn, in attenuating mitochondrial dysfunction caused by CL deficiency

Read more

Summary

Ethanolamine rescue of cardiolipin deficiency

Like CL, phosphatidylethanolamine (PE) is required for optimal mitochondrial bioenergetics by preserving the catalytic activities of the MRC complexes [31,32,33], whereas PC has been shown to be redundant as far as MRC function and assembly is concerned [31, 34, 35] Both PE and CL are synthesized in situ, unlike other mitochondrial phospholipids (Fig. 1). In addition to the mitochondrial pathway, PE can be biosynthesized either by the nonmitochondrial ethanolamine–Kennedy pathway or by a lyso-PE–requiring pathway (Fig. 1) Because of their common site of biosynthesis, reciprocal regulation of their levels, and the propensity to form nonbilayer structures, PE and CL have been proposed to have overlapping functions (36 –43). Our work identifies a novel role of Etn as a regulator of MRC biogenesis

Results
Discussion
Experimental procedures
Yeast strains
Primers used in this study
Mitochondrial isolation
Mitochondrial and cellular phospholipid measurements
Quantification of protein carbonyl content
Mass spectrometry

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call

Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.