Assembly of the complexes of oxidative phosphorylation triggers the remodeling of cardiolipin

Abstract

Cardiolipin (CL) is a mitochondrial phospholipid with a very specific and functionally important fatty acid composition, generated by tafazzin. However, in vitro tafazzin catalyzes a promiscuous acyl exchange that acquires specificity only in response to perturbations of the physical state of lipids. To identify the process that imposes acyl specificity onto CL remodeling in vivo, we analyzed a series of deletions and knockdowns in Saccharomyces cerevisiae and Drosophila melanogaster, including carriers, membrane homeostasis proteins, fission-fusion proteins, cristae-shape controlling and MICOS proteins, and the complexes I–V. Among those, only the complexes of oxidative phosphorylation (OXPHOS) affected the CL composition. Rather than any specific complex, it was the global impairment of the OXPHOS system that altered CL and at the same time shortened its half-life. The knockdown of OXPHOS expression had the same effect on CL as the knockdown of tafazzin in Drosophila flight muscles, including a change in CL composition and the accumulation of monolyso-CL. Thus, the assembly of OXPHOS complexes induces CL remodeling, which, in turn, leads to CL stabilization. We hypothesize that protein crowding in the OXPHOS system imposes packing stress on the lipid bilayer, which is relieved by CL remodeling to form tightly packed lipid–protein complexes.

Absolute yeast mitochondrial proteome quantification reveals trade-off between biosynthesis and energy generation during diauxic shift

“…5A), probably due to the majority of mitochondrial remodeling occurring already during the diauxic shift. Due to its conical shape, CL is known to be abundant in areas of high membrane curvature; moreover, this lipid has been implicated in the stabilization of individual complexes of the respiratory chain (39). We found that as cells shift toward respiration, the acyl-chain composition of the CL species also moves toward a higher degree of unsaturation ( Fig.…”

“…5 C and D). It has previously been speculated that the increase in CL unsaturation enables an increase in membrane fluidity, in turn allowing cristae to increase in curvature and accommodate more ATP synthase for respiration (39). This observation toward CL reconfiguration was further supported by the proteomic data, which showed an up-regulation of the Mitochondrial CL-specific phospholipase Cld1; the Mitochondrial phosphatidylglycerolphosphatase (PGP phosphatase) Gep4; the Phosphatidylglycerolphosphate synthase Pgs1, a rate-limiting step in the synthesis of CL; the Mitochondrial phosphatidate cytidylyltransferase (CDP-DAG synthase) Tam41, also required for CL biosynthesis; and the Lysophosphatidylcholine acyltransferase Taz1, involved in the CL acyl-chain remodeling (Fig.…”

Shaping the mitochondrial inner membrane in health and disease

“…Pointing to the importance of membrane morphology for cardiolipin biogenesis, a recent study found that cardiolipin levels are strongly reduced in cells lacking both proposed pathways for cristae formation, the Mgm1‐dependent pathway and the MICOS/phospholipid import‐dependent pathway (see section ‘Inner membrane dynamics’) . Similarly, cardiolipin remodelling and stability are severely affected in mutants with global defects of the respiratory chain, indicating that morphology and/or the high protein:lipid ratio of the inner membrane is required for cardiolipin metabolism .…”

“…In addition, the yeast inner membrane protein Mdm33 may enable inner membrane fission by regulating phospholipid homoeostasis and compartmentalization, possibly together with the prohibitins that are amongst Mdm33's interaction partners . Thus, phospholipid synthesis and remodelling may take place in specialized membrane subdomains that are maintained by membrane shaping or scaffolding proteins .…”

The mitochondria-targeted peptide SS-31 binds lipid bilayers and modulates surface electrostatics as a key component of its mechanism of action

“…CL plays a central role in many mitochondrial processes, including apoptosis, mitophagy, signaling, fission/fusion dynamics, and energy metabolism (14,15). Within the protein-rich MIM, CL mediates many interactions with peripheral and integral membrane proteins (16,17), underpinning its role in the assembly of OXPHOS complexes into supercomplexes (18,19).…”