Mindong Ren

Research Associate Professor, Department of Anesthesiology, Perioperative Care, and Pain Medicine

Research Associate Professor, Department of Cell Biology

Keywords
role of cardiolipin in health and disease
Summary

As the signature phospholipid of mitochondria membranes, cardiolipin owes its reputation in large part to the important mitochondrial proteins it associates with. The list of proteins that bind cardiolipin with high affinity is long and includes, among others, the respiratory complexes I, III, IV, and V, the carrier family (ADP?ATP-carrier, phosphate carrier, uncoupling protein), and two peripheral membrane proteins (cytochrome c and creatine kinase). By stabilizing higher order assemblies of respiratory complexes, called supercomplexes, with the major ADP/ATP carrier, cardiolipin significantly improves the efficiency and adaptability of the oxidative phosphorylation machinery. It is thus not surprising that derangements of cardiolipin metabolism are associated with a plethora of pathological states including ischemia/reperfusion injury, heart failure, inherited and diabetic cardiomyopathy, and cancer. However, the precise role of cardiolipin in these complex diseases has been mainly a matter of speculation. It is this gap in our understanding of cardiolipin?s role in health and disease that our research aims to fill. To simplify the matter, we chose to study Barth syndrome (BTHS), an inherited cardiomyopathy with its primary defect in cardiolipin metabolism. BTHS is caused by mutations in tafazzin gene, which lead to severe cardiolipin deficiency. Previously, using a Drosophila model, we established the causal role of cardiolipin deficiency in the pathogenesis of the disease and showed that cardiolipin deficiency disrupts the supramolecular organization of ATP synthase in mitochondria and diminishes the mitochondrial respiratory activity. In tafazzin-deficient mammalian cells in culture, we demonstrated that diminished mitochondrial respiratory activity is accompanied by elevated ROS production. Overall, the emerging pathogenic pathway is that of cardiolipin deficiency → abnormal mitochondrial supercomplex assembly → reduced mitochondrial oxygen consumption rate and elevated reactive oxygen species (ROS) production → cardiomyopathy. Recently, we characterized an inducible tafazzin-knockdown transgenic mouse model and showed that it recapitulates all the salient features of the cardiomyopathy in BTHS. We are carrying out systematic investigations of the pathogenic mechanism of BTHS-associated cardiomyopathy in this model. The outcome of this project will be significant because new understanding gained from this model will not only elucidate the pathogenesis of BTHS but also shed light on the mechanisms of common diseases such as diabetic cardiomyopathy and heart failure, where cardiolipin deficiency has been implicated as an important contributing factor.

Phone

212-263-5947

Academic office

550 First Avenue

Sixth Floor, Room 614

New York, NY 10016

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Research Associate Professor, Department of Anesthesiology, Perioperative Care, and Pain Medicine

Research Associate Professor, Department of Cell Biology

Schlame, Michael; Xu, Yang; Ren, Mindong

Journal of biological chemistry. 2017 Feb 15; 292(13):5499-5506

Xu, Yang; Phoon, Colin K L; Berno, Bob; D'Souza, Kenneth; Hoedt, Esthelle; Zhang, Guoan; Neubert, Thomas A; Epand, Richard M; Ren, Mindong; Schlame, Michael

Nature chemical biology. 2016 Aug; 12(8):641-647

Content of Plasmalogen Lipids Markedly Decreases in Barth Syndrome [Meeting Abstract]

Kimura, Tomohiro; Kimura, Atsuko; Berno, Bob; Ren, Mindong; Schlame, Michael; Epand, Richard M

Biophysical journal. 2016 FEB 16; 110(3):84A-84A

Xu, Yang; Malhotra, Ashim; Claypool, Steven M; Ren, Mindong; Schlame, Michael

Mitochondrion. 2015 Mar; 21:27-32

Ren, Mindong; Phoon, Colin K L; Schlame, Michael

Progress in lipid research. 2014 Jul; 55:1-16

BARTH SYNDROME, A MITOCHONDRIAL DISEASE AFFECTING CARDIOLIPIN AND MEMBRANE CURVATURE [Meeting Abstract]

Xu, Y.; Ren, M.; Schlame, M.

Anesthesia & analgesia. 2013 May; 116 1 1:75-75

Schlame, Michael; Acehan, Devrim; Berno, Bob; Xu, Yang; Valvo, Salvatore; Ren, Mindong; Stokes, David L; Epand, Richard M

Nature chemical biology. 2012 Oct; 8(10):862-869

Schlame, Michael; Blais, Steven; Edelman-Novemsky, Irit; Xu, Yang; Montecillo, Fleurise; Phoon, Colin K L; Ren, Mindong; Neubert, Thomas A

Chemistry & physics of lipids. 2012 Jul; 165(5):512-519