Different opinion on the reported role of Poldip2 and ACSM1 in a mammalian lipoic acid salvage pathway controlling HIF-1 activation

Paredes et al. (1) describe polymerase-δ interacting protein 2 (Poldip2) as a novel regulator of mitochondrial lipoylationthrough stabilization of Ac-CoA synthetase medium-chain family member 1 (ACSM1). We have several concerns with their proposed model based on the following reasons. Prior mammalian and yeast biochemical studies are not consistent with a significant physiological role for lipoate scavenging in eukaryotes (2, 3). Genetic depletion or germline mutationsin de novo lipoic acidsynthesis enzymes (LIAS, LIPT1, and LIPT2) result in loss of mitochondrial lipoylation, respiration, and developmental defects in mammals, which are not reversed with exogenous lipoic acid(2 … [↵][1]1To whom correspondence may be addressed. Email: dieckman{at}email.arizona.edu, alexander.kastaniotis{at}oulu.fi, or jan33{at}cam.ac.uk. [1]: #xref-corresp-1-1