Regulation of mitochondrial metabolism and its role in human disease

Our research goal is to characterize the role of Magmas in cell proliferation, differentiation and survival.  Magmas is an essential, highly conserved nuclear encoded mitochondrial protein present in all eukaryotic cells.  The high degree of conservation is demonstrated by the ability human of Magmas to substitute for its ortholog in yeast (Pam16).

Magmas is involved in two distinct but related functions: protein import into the inner mitochondrial membrane and regulation of oxidative phosphorylation.  Magmas essential activity is believed to be controlling the ATPase motor that drives movement of peptides through the TIM23 complex into the mitochondrial matrix.  In contrast, Magmas regulates oxidative phosphorylation (ox-phos) via interactions with the respiratory complexes present in the inner mitochondrial membrane.  Studies with a temperature sensitive mutation showed that altered sphingolipid metabolism is likely a key component in mediating the essential functions of Magmas.

Magmas activity requires dimerization with either DnaJC15 or DnaJC19.   We developed and synthesized a compound that inhibits Magmas dimerization.  It can be administered orally and has favorable CNS penetration.  The inhibitor reduces ox-phos activity in human glioma cell lines while glycolysis is largely spared.  It also replicates the mitochondrial respiratory phenotype of RNAi knockdown of Drosophila black-pearl (Magmas ortholog) in S2 cells.  The effects of the inhibitor on mitochondrial ox-phos dependent functions in S2 cells occur before any effects on protein import.  

Magmas and its binding partners have clinical relevance in several human diseases. Three different Magmas point mutations cause Autosomal Recessive Spondylometaphyseal Dysplasia, and mutations in DnaJC19 results in a dilated cardiomyopathy syndrome.  

Elevated levels of Magmas are observed in untreated prostate and ovarian cancer and glioblastoma samples.  Increased Magmas expression has been shown to protect against apoptosis.  In human ovarian cell lines chemotherapy induces Magmas expression in vitro and in vivo.  Interestingly, the Magmas inhibitor decreases the viability of a carboplatin resistant human ovarian cell line to a much greater extent than carboplatin sensitive cells and has minimal effects on normal cells. Platin resistance is a strong prognostic factor for poor survival in ovarian cancer patients.  

DnaJC15 deficiency is associated with chemotherapy resistance in breast cancer, while low DnaJC19 levels in lung cancer correlates with increased progression free survival. 

Our current studies focus on a genetic approach to characterize Magmas effects on several mitochondrial metabolic pathways and its role in cancer pathogenesis and treatment.

Selected Publications:

Jubinsky PT, Messer A, Bender J, Witte DP, Hawley R, Short MK.  Isolation and characterization of Magmas, a novel mitochondrial protein involved in GM-CSF signal transduction. Exp. Hematol 291392-1402, 2001.

Jubinsky PT, Short MK, Mutema G, Witte DP. Developmental expression of Magmas in murine tissues and its co-expression with the GM-CSF receptor.  J Histochem Cytochem 51:585-596, 2003.

Jubinsky PT, Short MK, Mutema G, Morris RE, Ciraolo GM, Li M.  Magmas expression in neoplastic human prostate. J Mol Histol 36:69-75, 2005.

Peng J, Huang C-H, Short MK, Jubinsky PT. Magmas gene structure and evolution.  In

Silico Biol 5:251-263, 2005.

Jubinsky PT, Short MK, Ghanem M, Das BC.  Design, synthesis and biological activity of novel Magmas Inhibitors.  Bioorg Med Chem Lett 21:3479-3482, 2011.

Roy S, Short MK, Stanley ER, Jubinsky PT.  Essential role of Drosophila black-pearl is mediated by its effects on mitochondrial respiration.  FASEB J  26:3822-33, 2012.

Short MK, Hallett JP, Tar K, Dange T, Schmidt M, Moir R, Willis IM, Jubinsky PT.  The Yeast Magmas ortholog Pam16 has an essential function in fermentative growth that involves sphingolipid metabolism.  Plos One 7: e39428, 2012.

Ahmed N, Kadife E, Raza A, Short M, Jubinsky PT, Kannourakis G. Ovarian Cancer, Cancer Stem Cells and Current Treatment Strategies: A Potential Role of Magmas in the Current Treatment Methods.  Cells 9: 719, 2020.