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Cardiolipin prolongs the lifetimes of respiratory proteins in Drosophila flight muscle

Ren, Mindong; Xu, Yang; Phoon, Colin K L; Erdjument-Bromage, Hediye; Neubert, Thomas A; Schlame, Michael
Respiratory complexes and cardiolipins have exceptionally long lifetimes. The fact that they co-localize in mitochondrial cristae raises the question of whether their longevities have a common cause and whether the longevity of OXPHOS proteins is dependent on cardiolipin. To address these questions, we developed a method to measure side-by-side the half-lives of proteins and lipids in wild-type Drosophila and cardiolipin-deficient mutants. We fed adult flies with stable isotope-labeled precursors (13C6
PMCID:10622840
PMID: 37690688
ISSN: 1083-351x
CID: 5594302

The critical role of cardiolipin in metazoan differentiation, development, and maturation

Olivar-Villanueva, Melissa; Ren, Mindong; Schlame, Michael; Phoon, Colin K L
Cardiolipins are phospholipids that are central to proper mitochondrial functioning. Because mitochondria play crucial roles in differentiation, development, and maturation, we would also expect cardiolipin to play major roles in these processes. Indeed, cardiolipin has been implicated in the mechanism of three human diseases that affect young infants, implying developmental abnormalities. In this review, we will: (1) Review the biology of cardiolipin; (2) Outline the evidence for essential roles of cardiolipin during organismal development, including embryogenesis and cell maturation in vertebrate organisms; (3) Place the role(s) of cardiolipin during embryogenesis within the larger context of the roles of mitochondria in development; and (4) Suggest avenues for future research.
PMID: 36692477
ISSN: 1097-0177
CID: 5426542

Why Don't More Mitochondrial Diseases Exhibit Cardiomyopathy?

Singh, Nina; Ren, Mindong; Phoon, Colin K L
BACKGROUND:Although the heart requires abundant energy, only 20-40% of children with mitochondrial diseases have cardiomyopathies. METHODS:We looked for differences in genes underlying mitochondrial diseases that do versus do not cause cardiomyopathy using the comprehensive Mitochondrial Disease Genes Compendium. Mining additional online resources, we further investigated possible energy deficits caused by non-oxidative phosphorylation (OXPHOS) genes associated with cardiomyopathy, probed the number of amino acids and protein interactors as surrogates for OXPHOS protein cardiac "importance", and identified mouse models for mitochondrial genes. RESULTS:< 0.05). Mouse models exhibiting cardiomyopathy were found for 52/241 mitochondrial genes, shedding additional insights into biological mechanisms. CONCLUSIONS:While energy generation is strongly associated with cardiomyopathy in mitochondrial diseases, many energy generation defects are not linked to cardiomyopathy. The inconsistent link between mitochondrial disease and cardiomyopathy is likely to be multifactorial and includes tissue-specific expression, incomplete clinical data, and genetic background differences.
PMCID:10144188
PMID: 37103033
ISSN: 2308-3425
CID: 5465302

Cardiolipin metabolism regulates expression of muscle transcription factor MyoD1 and muscle development

Vo, Linh; Schmidtke, Michael W; Da Rosa-Junior, Nevton T; Ren, Mindong; Schlame, Michael; Greenberg, Miriam L
The mitochondrial phospholipid cardiolipin (CL) is critical for numerous essential biological processes, including mitochondrial dynamics and energy metabolism. Mutations in the CL remodeling enzyme TAFAZZIN cause Barth syndrome, a life-threatening genetic disorder that results in severe physiological defects, including cardiomyopathy, skeletal myopathy, and neutropenia. To study the molecular mechanisms whereby CL deficiency leads to skeletal myopathy, we carried out transcriptomic analysis of the TAFAZZIN-knockout (TAZ-KO) mouse myoblast C2C12 cell line. Our data indicated that cardiac and muscle development pathways are highly decreased in TAZ-KO cells, consistent with a previous report of defective myogenesis in this cell line. Interestingly, the muscle transcription factor myoblast determination protein 1 (MyoD1) is significantly repressed in TAZ-KO cells and TAZ-KO mouse hearts. Exogenous expression of MyoD1 rescued the myogenesis defects previously observed in TAZ-KO cells. Our data suggest that MyoD1 repression is caused by upregulation of the MyoD1 negative regulator, homeobox protein Mohawk, and decreased Wnt signaling. Our findings reveal, for the first time, that CL metabolism regulates muscle differentiation through MyoD1 and identify the mechanism whereby MyoD1 is repressed in CL-deficient cells.
PMCID:9999232
PMID: 36739949
ISSN: 1083-351x
CID: 5447962

The mystery of mitochondrial plasticity: TMBIM5 integrates metabolic state and proteostasis

Ren, Mindong; Schlame, Michael
Recent work identifies TMBIM5 as inner mitochondrial membrane Ca2+ /H+ exchanger, linking hyperpolarisation regulation to proteome control and energy metabolism.
PMID: 35912455
ISSN: 1460-2075
CID: 5287822

Genetic Basis of Left Ventricular Noncompaction

Rojanasopondist, Pakdee; Nesheiwat, Leigh; Piombo, Sebastian; Porter, George A; Ren, Mindong; Phoon, Colin K L
BACKGROUND:Left ventricular noncompaction (LVNC) is the third most common pediatric cardiomyopathy characterized by a thinned myocardium and prominent trabeculations. Next-generation genetic testing has led to a rapid increase in the number of genes reported to be associated with LVNC, but we still have little understanding of its pathogenesis. We sought to grade the strength of the gene-disease relationship for all genes reported to be associated with LVNC and identify molecular pathways that could be implicated. METHODS:Following a systematic PubMed review, all genes identified with LVNC were graded using a validated, semi-quantitative system based on all published genetic and experimental evidence created by the Clinical Genome Resource (ClinGen). Genetic pathway analysis identified molecular processes and pathways associated with LVNC. RESULTS:We identified 189 genes associated with LVNC: 11 (6%) were classified as definitive, 21 (11%) were classified as moderate, and 140 (74%) were classified as limited, but 17 (9%) were classified as no evidence. Of the 32 genes classified as definitive or moderate, the most common gene functions were sarcomere function (n=11; 34%), transcriptional/translational regulator (n=6; 19%), mitochondrial function (n=3; 9%), and cytoskeletal protein (n=3; 9%). Furthermore, 18 (56%) genes were implicated in noncardiac syndromic presentations. Lastly, 3 genetic pathways (cardiomyocyte differentiation via BMP receptors, factors promoting cardiogenesis in vertebrates, and Notch signaling) were found to be unique to LVNC and not overlap with pathways identified in dilated cardiomyopathy and hypertrophic cardiomyopathy. CONCLUSIONS:LVNC is a genetically heterogeneous cardiomyopathy. Distinct from dilated or hypertrophic cardiomyopathies, LVNC appears to arise from abnormal developmental processes.
PMID: 35549379
ISSN: 2574-8300
CID: 5214612

LPGAT1 controls the stearate/palmitate ratio of phosphatidylethanolamine and phosphatidylcholine in sn-1 specific remodeling

Xu, Yang; Miller, Paighton C; Phoon, Colin K L; Ren, Mindong; Nargis, Titli; Rajan, Sujith; Hussain, M Mahmood; Schlame, Michael
Most mammalian phospholipids contain a saturated fatty acid at the sn-1 carbon atom and an unsaturated fatty acid at the sn-2 carbon atom of the glycerol backbone group. While the sn-2 linked chains undergo extensive remodeling by deacylation and reacylation (Lands cycle), it is not known how the composition of saturated fatty acids is controlled at the sn-1 position. Here, we demonstrate that lysophosphatidylglycerol acyltransferase 1 (LPGAT1) is an sn-1 specific acyltransferase that controls the stearate/palmitate ratio of phosphatidylethanolamine (PE) and phosphatidylcholine. Bacterially expressed murine LPGAT1 transferred saturated acyl-CoAs specifically into the sn-1 position of lysophosphatidylethanolamine (LPE) rather than lysophosphatidylglycerol and preferred stearoyl-CoA over palmitoyl-CoA as the substrate. In addition, genetic ablation of LPGAT1 in mice abolished 1-LPE:stearoyl-CoA acyltransferase activity and caused a shift from stearate to palmitate species in PE, dimethyl-PE, and phosphatidylcholine. Lysophosphatidylglycerol acyltransferase 1 KO mice were leaner and had a shorter life span than their littermate controls. Finally, we show that total lipid synthesis was reduced in isolated hepatocytes of LPGAT1 knockout mice. Thus, we conclude that LPGAT1 is an sn-1 specific LPE acyltransferase that controls the stearate/palmitate homeostasis of PE and the metabolites of the PE methylation pathway and that LPGAT1 plays a central role in the regulation of lipid biosynthesis with implications for body fat content and longevity.
PMID: 35131264
ISSN: 1083-351x
CID: 5175992

A simple mechanistic explanation for Barth syndrome and cardiolipin remodeling

Xu, Yang; Phoon, Colin K L; Ren, Mindong; Schlame, Michael
Barth syndrome is a multisystem disorder caused by an abnormal metabolism of the mitochondrial lipid cardiolipin. In this review, we discuss physical properties, biosynthesis, membrane assembly, and function of cardiolipin. We hypothesize that cardiolipin reduces packing stress in the inner mitochondrial membrane, which arises as a result of protein crowding. According to this hypothesis, patients with Barth syndrome are unable to meet peak energy demands because they fail to concentrate the proteins of oxidative phosphorylation to a high surface density in the inner mitochondrial membrane.
PMID: 34611930
ISSN: 1573-2665
CID: 5067722

Condensed Mitochondria Assemble Into the Acrosomal Matrix During Spermiogenesis

Ren, Mindong; Xu, Yang; Phoon, Colin K L; Erdjument-Bromage, Hediye; Neubert, Thomas A; Rajan, Sujith; Hussain, M Mahmood; Schlame, Michael
Mammalian spermatogenesis is associated with the transient appearance of condensed mitochondria, a singularity of germ cells with unknown function. Using proteomic analysis, respirometry, and electron microscopy with tomography, we studied the development of condensed mitochondria. Condensed mitochondria arose from orthodox mitochondria during meiosis by progressive contraction of the matrix space, which was accompanied by an initial expansion and a subsequent reduction of the surface area of the inner membrane. Compared to orthodox mitochondria, condensed mitochondria respired more actively, had a higher concentration of respiratory enzymes and supercomplexes, and contained more proteins involved in protein import and expression. After the completion of meiosis, the abundance of condensed mitochondria declined, which coincided with the onset of the biogenesis of acrosomes. Immuno-electron microscopy and the analysis of sub-cellular fractions suggested that condensed mitochondria or their fragments were translocated into the lumen of the acrosome. Thus, it seems condensed mitochondria are formed from orthodox mitochondria by extensive transformations in order to support the formation of the acrosomal matrix.
PMCID:9068883
PMID: 35531097
ISSN: 2296-634x
CID: 5214072

Neurological & psychological aspects of Barth syndrome: Clinical manifestations and potential pathogenic mechanisms

Olivar-Villanueva, Melissa; Ren, Mindong; Phoon, Colin K L
Barth syndrome is a rare X-linked multisystem mitochondrial disease that is caused by variants in the tafazzin gene leading to deficient and abnormal cardiolipin. Previous research has focused on the cardiomyopathy and neutropenia in individuals with Barth syndrome, yet just as common are the least explored neurological aspects of Barth syndrome. This review focuses on the major neuropsychological and neurophysiological phenotypes that affect the quality of life of individuals with Barth syndrome, including difficulties in sensory perception and feeding, fatigue, and cognitive and psychological challenges. We propose selected pathogenetic mechanisms underlying these phenotypes and draw parallels to other relevant disorders. Finally, avenues for future research are also suggested.
PMID: 34197965
ISSN: 1872-8278
CID: 5003722