Sheu Research

Contact

Name: Shey-Shing Sheu, PhD
Positions:
  • William Wikoff Smith Professor of Cardiovascular Research,
  • Associate Director

1020 Locust Street
543D
Philadelphia , PA 19107

Contact Number(s):

Highlighted Publications

Jhun BS, O-Uchi J, Adaniya SM, Mancini TJ, Cao JL, King ME, Landi AK, Ma H, Shin M, Yang D, Xu X, Yoon Y, Choudhary G, Clements RT, Mende U, Sheu SS. Protein kinase D activation induces mitochondrial fragmentation and dysfunction in cardiomyocytes. J Physiol. 596(5):827-855, 2018.

Abnormal mitochondrial morphology and function in cardiomyocytes are frequently observed under persistent Gq protein-coupled receptor (Gq PCR) stimulation. We demonstrate that a downstream kinase of Gq PCR, protein kinase D (PKD) induces mitochondrial fragmentation via phosphorylation of dynamin-like protein 1 (DLP1), a mitochondrial fission protein.

 

Sergio De La Fuente, Jonathan P. Lambert, Zuzana Nichtova, Celia Fernandez Sanz, John W. Elrod, Shey-Shing Sheu, and György Csordás. The spatial separation of mitochondrial calcium uptake and extrusion enhances energy-efficient mitochondrial calcium signaling in the heart. Cell Report 24(12):3099-3107, 2018.

Mitochondrial Ca2+ elevations enhance ATP production, but uptake must be balanced by efflux to avoid overload. Uptake is mediated by the mitochondrial Ca2+ uniporter channel complex (MCUC), and extrusion is mainly controlled by the Na+/Ca2+ exchanger (NCLX). MCUC forms hotspots at the cardiac mitochondria-junctional SR (jSR) association to locally receive Ca2+ signals, however, our fractionation-based assays reveal that extensively jSR-associated mitochondrial segments contain a minor portion of NCLX and lack Na+-dependent Ca2+ extrusion.

Hurst S, Baggett A, Csordas G, Sheu SS. SPG7 targets the m-AAA protease complex to process MCU for uniporter assembly, Ca2+ influx, and regulation of mPTP opening. J Biol Chem. 12;294(28):10807-10818, 2019.

The mitochondrial matrix ATPase associated with diverse cellular activities (m-AAA) protease spastic paraplegia 7 (SPG7) has been recently implicated as either a negative or positive regulatory component of the mitochondrial permeability transition pore (mPTP). We found that loss of the SPG7 gene increased resistance to Ca2+-induced mPTP opening. However, this occurs independently of cyclophilin D. Instead, it is through decreased mitochondrial Ca2+ concentrations and subsequent adaptations mediated by the impaired formation of functional mitochondrial Ca2+ uniporter complexes.

Hu Q, Zhang H, Gutierrez Cortes N, Wu D, Wang P, Zhang J, Mattison JA, Smith E, Bettcher LF, Wang M, Lakatta EG, Sheu SS, Wang W. Increased Drp1 acetylation by lipid overload induces cardiomyocyte death and heart dysfunction. Circ. Res. 119.315252, [Epub ahead of print], 2020.

The findings uncover a novel mechanism that contributes to lipid overload-induced heart hypertrophy and dysfunction. Excessive lipid supply created an intracellular environment that facilitated Drp1 acetylation, which, in turn, increased its activity and mitochondrial translocation, resulting in cardiomyocyte dysfunction and death. Thus, Drp1 may be a critical mediator of lipid overload-induced heart dysfunction as well as a potential target for therapy.

Recent Publications

Regulation of Oxidative Phosphorylation of Liver Mitochondria in Sepsis

Elevated MCU Expression by CaMKIIδB Limits Pathological Cardiac Remodeling

Defective dimerization of FoF1-ATP synthase secondary to glycation favors mitochondrial energy deficiency in cardiomyocytes during aging

Activation of Crtc2/Creb1 in skeletal muscle enhances weight loss during intermittent fasting

The role of mitochondria in metabolic disease: a special emphasis on heart dysfunction

Electrophysiological properties of the mitochondrial permeability transition pores: Channel diversity and disease implication

Unsolved mysteries and controversies of mitochondria in the heart – A virtual special issue in JMCC: Part IV

Phosphorylation of cyclophilin D at serine 191 regulates mitochondrial permeability transition pore opening and cell death after ischemia-reperfusion

Unsolved mysteries and controversies of mitochondria in the heart– A Virtual Special Issue in JMCC: Part III

Unsolved mysteries and controversies of mitochondria in the heart – A virtual special issue in JMCC: Part II

The short variant of optic atrophy 1 (OPA1) improves cell survival under oxidative stress

Unsolved mysteries and controversies of mitochondria in the heart – A virtual special issue in JMCC

Why don't mice lacking the mitochondrial Ca2+ uniporter experience an energy crisis?

Increased Drp1 acetylation by lipid overload induces cardiomyocyte death and heart dysfunction

Unlocking the Secrets of Mitochondria in the Cardiovascular System: Path to a Cure in Heart Failure—A Report from the 2018 National Heart, Lung, and Blood Institute Workshop

Trpm2 enhances physiological bioenergetics and protects against pathological oxidative cardiac injury: Role of Pyk2 phosphorylation

Introduction

SPG7 targets the m-AAA protease complex to process MCU for uniporter assembly, Ca2 influx, and regulation of mitochondrial permeability transition pore opening

Mitochondrial Ca2+ concentrations in live cells: quantification methods and discrepancies

SR-mitochondria communication in adult cardiomyocytes: A close relationship where the Ca 2+ has a lot to say

Spatial Separation of Mitochondrial Calcium Uptake and Extrusion for Energy-Efficient Mitochondrial Calcium Signaling in the Heart

Regulation of mitochondrial bioenergetics by the non-canonical roles of mitochondrial dynamics proteins in the heart

Protein kinase D activation induces mitochondrial fragmentation and dysfunction in cardiomyocytes

Organellar Ion Channels and Transporters

Fluorescence digital imaging microscopy- spatial distribution of CA2+ and H+ in single cells