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 G_q protein-coupled receptor (G_q PCR) stimulation. We demonstrate that a downstream kinase of G_q 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.