title: Cyclophilin-D: a resident regulator of mitochondrial gene expression.
abstract: Cyclophilin-D (Cyp-D) is a mitochondrial matrix peptidyl-prolyl isomerase. Because cyclophilins can regulate nuclear gene expression, we examined whether Cyp-D could regulate mitochondrial gene expression. We demonstrated in HEK 293T cells that transfected Cyp-D interacts with mitochondrial transcription factors B1 and B2 (TFB2M) but not with mitochondrial transcription factor A. We also demonstrated that Cyp-D interacts in vivo with TFB2M. Genetic silencing of Cyp-D and pharmacologic inhibition of Cyp-D markedly reduced mitochondrial transcription to 18 ± 5% (P < 0.05) and 24 ± 3% (P < 0.05) of respective controls. The level of interaction between Cyp-D and TFB2M correlated with the level of nascent mitochondrial RNA intensity (r = 0.896; P = 0.0156). Cyp-D silencing down-regulated mitochondrial transcripts initiated from the heavy strand promoter 2 [i.e., NADH dehydrogenase 1 (ND1) by 11-fold, P < 0.005; cytochrome oxidase 1 (COX1) by 4-fold, P < 0.001; and ATP synthase subunit 6 (ATP6) by 6.5-fold, P < 0.005); but not NADH dehydrogenase 6 (ND6)], which is initiated from the light strand promoter. Cyp-D silencing reduced mitochondrial membrane potential and cellular oxygen consumption (from 59 ± 5 to 34 ± 1 µmol oxygen/min/10(6) cells, P < 0.001); the latter without a statistically significant reversal after uncoupling electron transport from ATP synthesis, consistent with down-regulation of electron transport complexes. Accordingly, these studies provide novel evidence that Cyp-D could play a key role in regulating mitochondrial gene expression.
authors.affiliation: *Department of Medicine and Resuscitation Institute, Center for Stem Cell and Regenerative Medicine, Department of Neuroscience, and H. M. Bligh Cancer Research Laboratories, Department of Microbiology and Immunology, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, USA; and Captain James A. Lovell Federal Health Care Center, North Chicago, Illinois, USA jeejabai.radhakrishnan@rosalindfranklin.edu raul.gazmuri@rosalindfranklin.edu.
authors.forename: Jeejabai
authors.initials: J
authors.lastname: Radhakrishnan
authors.affiliation: *Department of Medicine and Resuscitation Institute, Center for Stem Cell and Regenerative Medicine, Department of Neuroscience, and H. M. Bligh Cancer Research Laboratories, Department of Microbiology and Immunology, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, USA; and Captain James A. Lovell Federal Health Care Center, North Chicago, Illinois, USA.
authors.forename: Stanley
authors.initials: S
authors.lastname: Bazarek
authors.affiliation: *Department of Medicine and Resuscitation Institute, Center for Stem Cell and Regenerative Medicine, Department of Neuroscience, and H. M. Bligh Cancer Research Laboratories, Department of Microbiology and Immunology, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, USA; and Captain James A. Lovell Federal Health Care Center, North Chicago, Illinois, USA.
authors.forename: Bala
authors.initials: B
authors.lastname: Chandran
authors.affiliation: *Department of Medicine and Resuscitation Institute, Center for Stem Cell and Regenerative Medicine, Department of Neuroscience, and H. M. Bligh Cancer Research Laboratories, Department of Microbiology and Immunology, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, USA; and Captain James A. Lovell Federal Health Care Center, North Chicago, Illinois, USA jeejabai.radhakrishnan@rosalindfranklin.edu raul.gazmuri@rosalindfranklin.edu.
authors.forename: Raúl J
authors.initials: RJ
authors.lastname: Gazmuri
mesh_terms: D051545:Cyclooxygenase 1 / Q000235:genetics; D021983:Cyclophilins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D005786:Gene Expression Regulation; D020868:Gene Silencing; D050259:Genes, Mitochondrial; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D025261:Mitochondrial Proton-Translocating ATPases / Q000235:genetics; D009245:NADH Dehydrogenase / Q000235:genetics; D010085:Oxidative Phosphorylation; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D000097322:Peptidyl-Prolyl Isomerase D
chemical_list: D051545:Cyclooxygenase 1; D021983:Cyclophilins; D004268:DNA-Binding Proteins; D049452:Green Fluorescent Proteins; D008780:Methyltransferases; D024101:Mitochondrial Proteins; D025261:Mitochondrial Proton-Translocating ATPases; D009245:NADH Dehydrogenase; D014157:Transcription Factors; C501005:MT-ATP6 protein, human; C499632:TFB1M protein, human; C496511:PTGS1 protein, human; C462443:TFB2M protein, human; C114456:PPID protein, human; D000097322:Peptidyl-Prolyl Isomerase D; C515075:NADH dehydrogenase subunit 1, human
keywords: membrane potential; oxygen consumption; respiratory complexes; transcription