Edited by James Murray, PhD.
Thousands of researchers around the world are studying the connections between mitochondria, metabolism and disease. MitoNews summarizes a selection of the latest published findings and highlights how Abcam's MitoSciences range of research tools has contributed to this effort. The full list of 32 original research papers published this month using the MitoSciences range of products can be found here.
Past issues are available for review in the archives
Cytochrome c oxidase – expression and regulation
The mitochondrial inner membrane enzyme cytochrome c oxidase (CCO, COX, Complex IV) is the terminal electron accepting enzyme and rate limiting step in the respiratory chain, responsible for the consumption of >90% of cellular oxygen. The structure of this dimeric enzyme was solved in 1996 and consists of 13 different structural subunits, 3 of which are encoded by mitochondrial DNA. The enzyme contains 2 heme centers and 2 Cu proteins, CuA, heme a, and CuB-heme a3 with two tightly bound cardiolipin molecules necessary for activity. To assemble such complexity, a number of factors are required for correct folding of cytochrome c oxidase, including SURF1, SCO1, SCO2, COX10, COX15, and LRPPRC.
Mitochondrial genetic disease can arise from mutations in structural genes and assembly factors that result in decreased cytochrome c oxidase activity. In other diseases, decreased assembly and activity of cytochrome c oxidase has also been implicated by multiple groups in Alzheimer's disease. Conversely increased expression of nuclear encoded cytochrome c oxidase subunits in cancer cells has been shown in multiple studies
Regulation of cytochrome c oxidase activity occurs by at least three mechanisms. First, regulatory phosphorylation of several subunits has been identified (subunits I, IV and Va). Second, allosteric regulation occurs by the binding of ATP (inhibitor) or ADP (activator) to subunit IV, thereby matching energy production to energy demand. Third, the transcriptional regulation of nuclear and mitochondrial genes. Interestingly cytochrome c oxidase is the only respiratory chain enzyme which contains tissue specific, nuclear encoded, isoforms. Isoforms have been identified for subunits IV, VIa, VIIa, VIb, and VIII; however the regulatory function of these isoforms is unclear.
The best understood is subunit IV, which exists in a ubiquitous (IV-1) and lung specific isoform (IV-2). Interestingly the isoform IV-2 is also regulated by the oxygen sensing HIF transcriptional pathway.
This month, Huttemann et al. showed that lung tissue contains an equal amount of isoform IV-1 and IV-2 while other tissues contain almost exclusively IV-1. A mouse knockout in subunit IV-2 results in a 50% decrease in lung tissue COX activity when compared to control. This decrease is consistent with the relative specific activities of cytochrome c oxidase enzyme isolated from lung and liver tissues. The decreased cytochrome c oxidase activity in the mouse knockout resulted in reduced cellular ATP and lung function. The authors propose that since lung tissue has a relatively low mitochondrial capacity, a highly efficient cytochrome c oxidase may be necessary to compensate. The authors go on to propose that a potential therapeutic treatment for asthma may be the inhibition of cytochrome c oxidase activity in order to reduce cellular ATP levels, airway contraction and so provide asthma relief.
Cytochrome c oxidase subunit 4 isoform 2-knockout mice show reduced enzyme activity, airway hyporeactivity, and lung pathology FASEB J. 2012. Hüttemann M, Lee I, Gao X, Pecina P, Pecinova A, Liu J, Aras S, Sommer N, Sanderson TH, Tost M, Neff F, Aguilar-Pimentel JA, Becker L, Naton B, Rathkolb B, Rozman J, Favor J, Hans W, Prehn C, Puk O, Schrewe A, Sun M, Höfler H, Adamski J, Bekeredjian R, Graw J, Adler T, Busch DH, Klingenspor M, Klopstock T, Ollert M, Wolf E, Fuchs H, Gailus-Durner V, Hrabe de Angelis M, Weissmann N, Doan JW, Bassett DJ, Grossman LI.
Also this month, Chen et al. showed in non-small cell lung carcinoma cells a correlation between subunit Va expression, matrix metalloproteinase activity and Bcl2 expression. Knockdown of Va resulted in suppressed migration/invasion by these cells. Immunohistochemical staining of surgically resected lung adenocarcinomas in 250 consecutive patients also revealed that strong COX Va expression correlated positively with the status of lymph node metastasis.
The role of cytochrome c oxidase subunit Va in non small cell lung carcinoma cells: association with migration, invasion and prediction of distant metastasis. BMC Cancer. 2012. Chen WL, Kuo KT, Chou TY, Chen CL, Wang CH, Wei YH, Wang LS.
Also this month:
Oligomerization of heme o synthase in cytochrome oxidase biogenesis is mediated by cytochrome oxidase assembly factor Coa2. J Biol Chem 2012 Khalimonchuk O, Kim H, Watts T, Perez-Martinez X, Winge DR.
See also OXPHOS Complex I papers this month:
Proteomic and Metabolomic Analyses of MItochondrial Complex I-deficient Mouse Model Generated by Spontaneous B2 Short Interspersed Nuclear Element (SINE) Insertion into NADH Dehydrogenase (Ubiquinone) Fe-S Protein 4 (Ndufs4) Gene. JBC 2012. Leong DW, Komen JC, Hewitt CA, Arnaud E, McKenzie M, Phipson B, Bahlo M, Laskowski A, Kinkel SA, Davey GM, Heath WR, Voss AK, Zahedi RP, Pitt JJ, Chrast R, Sickmann A, Ryan MT, Smyth GK, Thorburn DR, Scott HS.
Mutant NADH dehydrogenase subunit 4 gene delivery to mitochondria by targeting sequence-modified adeno-associated virus induced visual loss and optic atrophy in mice. Mol Vis 2012. Yu H, Ozdemir SS, Koilkonda RD, Chou TH, Porciatti V, Chiodo V, Boye SL, Hauswirth WW, Lewin AS, Guy J.
Inhibition of complex I regulates the mitochondrial permeability transition through a phosphate-sensitive inhibitory site masked by cyclophilin D. BBA 2012. Li B, Chauvin C, De Paulis D, De Oliveira F, Gharib A, Viral G, Lablanche S, Leverve X, Bernardi P, Ovize M, Fontaine E.
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