Their work led to an The loss of Ups1 leads to decreased CL levels . Nonbilayer phospholipids of mitochondria However, deletion of UPS1 does not completely abro- distinguish between these two possibilities, we have gate CL biosynthesis, suggesting alternative modes of highlighted the instances where strong evidence for PA transport to the IMM.
Ups2, also known as Gep1, one or the other exists. In addition to these proteins, the same screen to the OMM, and the cristae, tube-like invaginations also identified a number of GEP proteins, including of the IMM that project into the matrix . The precise energetic state of the organelle, the overall structure of biochemical function of some of these GEP proteins in cristae is very much conserved—a dome-shaped tip the regulation of mitochondrial nonbilayer phospho- caps the tubular cristae . The enrichment of nonbi- lipids is yet to be delineated.
This question constant level .
For example, depletion of PE in ps- can be answered by electron microscopic observations d1D is always accompanied by an elevation in the of mitochondrial ultrastructure from CL- and PE-defi- levels of PC, whereas loss of CL in crd1D is accompa- cient mitochondria. Interestingly, in the yeast model, nied by increased PE and PG levels [15,60]. Currently, the loss of CL seems to have a very small effect on the molecular basis for homeostatic mechanisms that cristae length and the gross mitochondrial ultra struc- strictly maintain mitochondrial phospholipid levels ture  W.
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Basu Ball, unpublished results. However, remains unknown. Future research will be needed swirls, curls, or rings . Similarly, enlarged mito- to distinguish between these possibilities. The coordi- chondria with abnormal, circularly stacked cristae nate regulation of mitochondrial CL and PE levels were observed in BTHS patient cardiac cells  and suggests that a critical amount of these nonbilayer- in the muscle of a murine model of BTHS . These forming phospholipids is required for mitochondrial findings support a critical role of CL in cristae archi- function.
In contrast, our own work has shown that the gross mitochondrial ultra structure in the yeast mutants of PE, PC, and CL biosynthesis is highly Role of CL in mitochondrial structure resistant to perturbations in mitochondrial phospho- and function lipid composition  W. Basu Ball unpublished The availability of CL deficient cells in different model results.
One possible explanation of this divergent systems, including yeast, fly, mouse, and human observation between different species is that CL defi- patient cell lines, has proved invaluable in uncovering cient yeast accumulates PG and PE, which may com- the role of CL in mitochondrial function in different pensate for CL . In support of this argument, the organisms [21,61—63].
Below we provide key examples loss of both CL and PG in yeast pgs1D cells results in from the studies performed using these model systems aberrant mitochondria containing ring-like cristae, as well as in vitro experiments showing how CL influ- which are reminiscent of the MICOS mutants . It ences various aspects of mitochondrial structure and has also been shown that CL is required for the assem- function.
CL can impact mitochondrial function either bly of the MICOS subcomplex, thus it may mediate its through specific molecular interactions between itself impact on mitochondrial architecture in part via its and target proteins or by modulating the bulk proper- effect on assembly of the MICOS subcomplex . To conclusively determine the role of nonbilayer- involves Drp1, the protein that directly mediates the forming phospholipids in cristae architecture a fission process.
CL has been shown to mediate both psd1Dcrd1D double mutant would be required. A recent study by Stepanyants in this mutant can be exogenously controlled, as has et al. First Drp1 preferentially associates with CL localized at a high spatial density in the membrane bilayer. Thus, these bio- that are primed for fission . On the other hand physical properties of CL have the potential to impact phosphatidic acid PA , a relatively minor nonbilayer mitochondrial membrane dynamics.
Consistent with its constituent of the mitochondrial membranes, has biophysical characteristics, CL is critical for fusion of recently been shown to be a negative regulator of the inner membrane via its interaction with the dyna- mitochondrial fission . Once bound to the PA head group, the and Opa1 are mixed, maximum lipid mixing and mem- GTPase activity of Drp1 is inhibited, which in turn brane fusion is observed.
In trials when both the lipo- prevents mitochondrial division . Thus, two nonbi- some partners either lack Opa1 machinery or contain layer phospholipids of mitochondria, PA and CL, only a minimal amount of CL, no membrane fusion antagonistically regulate mitochondrial fission by dif- was observed. Interestingly, in this experimental set ferentially interacting with Drp1 GTPase. Taken up, the presence of Opa1 in one fusion partner and together, mitochondrial membrane fusion and fission high CL levels in the other is sufficient for membrane are modulated by local nonbilayer phospholipid con- fusion.
Thus, besides defining the minimal fusion centrations and are likely dependent on both specific machinery, these results suggest that a critical level of phospholipid:protein interactions as well as curvature CL alone primes the membrane for fusion. This find- stress induced by the promotion of local nonbilayer ing is an important advancement in our understanding structures.
Further- more, the authors went on to show that the acyl chain The exclusive presence of CL within membranes asso- length and saturation of CL also influences membrane ciated with energy transduction reactions suggests an fusion, with longer length and higher unsaturation intimate association of CL with bioenergetics.
The enhancing fusion. These in vitro findings were con- most striking evidence for the role of CL in influencing firmed in vivo using mitochondria from OPA1 and mitochondrial bioenergetics comes from the studies CLS1 cardiolipin synthase knockdown HeLa cells. The individual components of mitochon- for dimerization and activation of its GTPase activity drial respiratory chain MRC complexes assemble for membrane fusion . However, unlike OPA1, into supramolecular structures called supercomplexes.
Mgm1 works in trans . Thus, the role of CL in These respiratory supercomplexes are proposed to sta- mitochondrial fusion appears to be evolutionarily bilize individual MRC complexes, minimize the gener- conserved. Nonbilayer phospholipids of mitochondria efficiency by substrate channeling . In the yeast ished mitochondrial membrane potential . We refer readers to a more detailed CL has been shown to stabilize the respiratory super- review on specific interactions of CL with mitochon- complexes in both yeast and mammals [79—81]. Struc- drial integral membrane proteins published recently tural studies with purified yeast and bovine MRC .
Here, we provide key examples of specific interac- supercomplexes employing cryoelectron microscopy tions of CL with mitochondrial integral membrane have estimated the presence of 50 and molecules proteins that may indirectly influence mitochondrial of CL in yeast and bovine MRC supercomplexes, bioenergetics. This species of CL cannot purified yeast complexes, which showed that super- be replaced by either other species of CL or other complex formation specifically required the presence of phospholipids, emphasizing the requirement for speci- CL in liposomes .
A recent study has uncovered a role of CL in to directly interact with individual MRC complexes acetyl CoA biosynthesis via possible interaction with and influence their activities. CL has been shown to activity in yeast crd1D cells , although this could be be involved in the proper functioning of the mitochon- due to reduced expression of the MRC components, as drial translocase of outer membrane TOM and sort- has been shown in yeast cells devoid of both CL and ing and assembly machinery SAM , compromising the PG .
The presence of CL is observed in the cryo- efficient import of cytoplasmic proteins to mitochon- electron microscopic structures of complex III and dria . CL also impacts the translocation of pro- complex IV [82,83], and the topology of CL in com- teins across the IMM via translocase of the inner plex III and IV suggests that it is required for proton membrane Tim23 and the presequence translocase- conductance [87—89]. A decrease in CL, associated with complex II previously, in a recent caused by the loss of Ups1, alters the conformation of study complex II subunits reconstituted on phospho- Tim23, reducing its functional interaction with PAM lipid nanodiscs were shown to require CL for assembly and thereby decreasing mitochondrial protein import and activity .
Additionally, reduced membrane potential complexes define the role of CL in regulating mito- observed in CL-deficient cells also contributes to chondrial bioenergetics. The physiological conse- decreased mitochondrial protein import . Details quences of the loss of CL and, therefore, CL—MRC on how CL impacts mitochondrial protein import have interactions, have been studied by classical bioenerget- been recently reviewed . This phenotype is tance of mitochondrial CL in influencing the mito- exacerbated during high respiratory rates and by tem- chondrial quality control process through mitophagy, perature and osmotic stress [91,92].
Consistent with a selective degradation of mitochondria through these observations in the yeast system, ATP levels are autophagy.
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In an elegant study, Chu and colleagues reduced in TAZ-deficient cardiac fibroblasts . They further showed medium, this mutant exhibits a rapid loss of mitochon- that CL on the OMM is recognized by microtubule- drial DNA, confounding the interpretation of its role asociated protein-1 light chain 3 LC3 , which pro- in specific aspects of mitochondrial function [15,41].
The role of CL in mitophagy is likely depen- ple complexes of the MRC, which would mask a sub- dent on its specific interaction with LC3, which has tler role of PE in mitochondrial bioenergetics. In a CL binding sites required for mediating mitochondrial mouse model, it was shown that loss of the mam- degradation by mitophagy [,].
This limitation was overcome by using dria for mitophagy . In the case of yeast, the vations, a decrease in CL in TAZ-deficient primary loss of mitochondrial DNA can be overcome by using mouse embryonic fibroblasts, resulted in defective a defined synthetic growth media with a nonfer- mitophagosome biogenesis . This finding provides mentable carbon source. Both of these strategies were new insights into the possible role of mitophagy in employed recently in uncovering the role of mitochon- BTHS disease pathogenesis and suggests that pharma- drial PE.
Below, we discuss key findings from these cological stimulation of mitophagy may ameliorate this studies and refer readers to recent reviews for a more disease condition. The role of CL in mitophagy detailed description of the role of PE in cellular physi- appears to be conserved because a recent study showed ology [56,58].
Thus, genetic studies in different model systems have Mitochondrial ultrastructure in PE-deficient mitochon- uncovered important mechanisms underlying mito- dria has been determined in both yeast and mam- chondrial dysfunction and disease pathologies associ- malian cell lines.
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Going forward, developing a mitochondrial ultrastructure was largely unperturbed physiologically relevant small molecule that can pro- even with an almost fivefold reduction in mitochon- mote supercomplex formation, increase MRC complex drial PE levels , although this reduction in PE activities, and curb mitochondrial oxidative stress will levels was associated with a small but significant be required to ameliorate CL-associated mitochondrial decrease in cristae length .
In PISD knockdown dysfunction. Toward this goal, novel approaches and mammalian CHO-K1 cells, the reduction in mitochon- promising compounds have emerged . The apparent discrepancy between and function yeast and higher eukaryotic cells could be due to the Phosphatidylethanolamine is an ancient and ubiqui- ability of yeast cells to alter their phospholipid compo- tous phospholipid that is present in all membranes of sition in order to maintain optimal intrinsic membrane the cell.
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Unlike CL, the specific role of PE in mito- curvature. For example, the loss of mitochondrial PE chondrial structure and function has not been exam- is accompanied by an increase in PC levels and vice- ined until recently. This is because multiple versa, such that the overall phospholipid content of biochemical pathways can synthesize PE and deletion mitochondria remains unaltered . The alteration in of the mitochondrial pathway of PE alone is not suffi- phospholipid content in phospholipid mutants is typi- cient to completely deplete mitochondrial PE levels cally accompanied by changes in the fatty acyl species, .