Diabetes Metab J.  2021 Nov;45(6):853-865. 10.4093/dmj.2021.0138.

Mitochondrial TFAM as a Signaling Regulator between Cellular Organelles: A Perspective on Metabolic Diseases

Affiliations
  • 1Department of Physiology, Yeungnam University College of Medicine, Daegu, Korea
  • 2Cardiovascular and Metabolic Disease Center, Smart Marine Therapeutic Center, Department of Physiology, College of Medicine, Inje University, Busan, Korea
  • 3Department of Internal Medicine, Uijeongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea

Abstract

Tissues actively involved in energy metabolism are more likely to face metabolic challenges from bioenergetic substrates and are susceptible to mitochondrial dysfunction, leading to metabolic diseases. The mitochondria receive signals regarding the metabolic states in cells and transmit them to the nucleus or endoplasmic reticulum (ER) using calcium (Ca2+) for appropriate responses. Overflux of Ca2+ in the mitochondria or dysregulation of the signaling to the nucleus and ER could increase the incidence of metabolic diseases including insulin resistance and type 2 diabetes mellitus. Mitochondrial transcription factor A (Tfam) may regulate Ca2+ flux via changing the mitochondrial membrane potential and signals to other organelles such as the nucleus and ER. Since Tfam is involved in metabolic function in the mitochondria, here, we discuss the contribution of Tfam in coordinating mitochondria-ER activities for Ca2+ flux and describe the mechanisms by which Tfam affects mitochondrial Ca2+ flux in response to metabolic challenges.

Keyword

Calcium; Cell nucleus; Diabetes mellitus, type 2; Endoplasmic reticulum; Mitochondria; TFAM protein

Figure

  • Fig. 1. Schematic illustration of the mechanism underlying the mitochondrial membrane potential (ΔΨm) and electron transport chain (ETC) as well as a summary of subunits of the four-ETCs and adenosine triphosphate (ATP) synthase (complex V) encoded by nuclear and mitochondrial genes. The five complexes are embedded in the inner mitochondrial membrane. ΔΨm is generated via a proton pump comprising complex I, III, and IV, and the electron is sequentially transferred from complex I to IV, referred to as the ETC. The proton pump-induced proton gradient between the intermembrane space and matrix generates ΔΨm. The flow of protons through ATP synthase from the intermembrane space to the matrix is coupled with ATP synthesis. Indicated below each complex is the number of protein subunits encoded by nuclear (nDNA) and mitochondrial genomes (mtDNA). OMM, outer mitochondrial membrane; IMM, inner mitochondrial membrane; NAD(H), nicotinamide adenine dinucleotide; CoQ, coenzyme Q; FAD(H), flavin adenine dinucleotide; Cyt C, cytochrome C; ADP, adenosine diphosphate .

  • Fig. 2. Mitochondria contacts endoplasmic reticulum (ER) and regulates cellular calcium (Ca2+) flux. Na+/Ca2+ exchanger (NCLX) regulates Ca2+ efflux from the mitochondria to the cytosol. The sarco/endoplasmic reticulum Ca2+ ATPase (Serca) in the ER membrane can take up Ca2+ into the ER lumen. Inositol triphosphate (IP3) binds to its own receptor (IP3R) leading to ER Ca2+ efflux in the cytosol or the mitochondria via a voltage-dependent anion channel (VDAC) at the outer mitochondrial membrane (OMM); in turn, the mitochondrial calcium uniporter (MCU) transfers it across the inner mitochondrial membrane (IMM). Ca2+ is necessary for the activation of pyruvate dehydrogenase (PDH), isocitrate dehydrogenase (IDH), and α-ketoglutarate (KGDH); thus, Ca2+ flux in the mitochondria is a key process for the tricarboxylic acid (TCA) cycle to provide nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH) for the electron transport chain (ETC). Mitofusin (MFN) induces mitochondria-ER physical tethering to provide a stable association.

  • Fig. 3. A schematic illustration of the hypothesized role of mitochondrial transcription factor A (Tfam). Mechanism by which Tfam sends calcium (Ca2+) signals to the nucleus. Na+/Ca2+ exchanger (NCLX) and mitochondrial calcium uniporter (MCU) are embedded at the inner mitochondrial membrane (IMM). The activity of these channels can be affected by ΔΨm flux, which can be regulated by Tfam. Thus, Tfam-driven ΔΨm can transmit Ca2+ signals via NCLX/voltage-dependent anion channel (VDAC) to the nucleus. Tfam can regulate the transcription of NCLX and sarco/endoplasmic reticulum Ca2+ ATPase (Serca); however, the specific mechanism is not clear in metabolic cells. Tfam increases calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ), 5’ adenosine monophosphate-activated protein kinase (AMPK) phosphorylation, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), nuclear respiratory factor 1 (NRF-1), and peroxisome proliferator-activated receptor delta (PPARδ). The Tfam-induced increase in these proteins seems to be regulated by Ca2+ signaling. ER, endoplasmic reticulum.

  • Fig. 4. A schematic illustration of the summary of the dysregulation of mitochondrial calcium (Ca2+) flux in type 2 diabetes mellitus (T2DM). Lower mitochondrial transcription factor A (Tfam) levels in T2DM may serially induce mitochondrial Ca2+ dysregulation through ΔΨm/Ca2+ channels. (1) Lower Tfam levels in mitochondria clearly reduce the mitochondrial complex that regulates proton pumps, (2) leading to dysregulation of ΔΨm that controls the Na+/Ca2+ exchanger (NCLX) channel. (3) Overload of Ca2+ induced by NCLX decreases tricarboxylic acid (TCA) cycle activity, resulting in reduced supply of nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH) for the electron transport chain (ETC) proton pump; especially, overloaded Ca2+ increases inner mitochondrial membrane (IMM) depolarization and decreases ΔΨm for NCLX activity. Overloaded Ca2+ in (3) matrix and (4) intermembrane space may trigger apoptosis. (5) Dysregulation of Ca2+ by inositol triphosphate receptor (IP3R) and sarco/endoplasmic reticulum Ca2+ ATPase (Serca) is clearly linked to mitochondrial dysfunction and metabolic disease. (6) Loss of mitofusin (MFN) downregulates stable contact of the mitochondria and endoplasmic reticulum (ER), leading to T2DM. (7) Overloaded Ca2+ in cytosol also increases the incidence of T2DM. (8) Loss of Ca2+ signaling into the nucleus from the mitochondria may inhibit the transcription of NCLX, Serca, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and peroxisome proliferator-activated receptor delta (PPARδ), (9) glucose transporter type 4 (GLUT4) expression is regulated by PPARδ. This can be a caused by a metabolic disease. MCU, mitochondrial calcium uniporter; VDAC, voltage-dependent anion channel.


Reference

1. Finsterer J. Overview on visceral manifestations of mitochondrial disorders. Neth J Med. 2006; 64:61–71.
2. Patti ME, Corvera S. The role of mitochondria in the pathogenesis of type 2 diabetes. Endocr Rev. 2010; 31:364–95.
Article
3. La Rovere RM, Roest G, Bultynck G, Parys JB. Intracellular Ca(2+) signaling and Ca(2+) microdomains in the control of cell survival, apoptosis and autophagy. Cell Calcium. 2016; 60:74–87.
4. Lanner JT, Katz A, Tavi P, Sandstrom ME, Zhang SJ, Wretman C, et al. The role of Ca2+ influx for insulin-mediated glucose uptake in skeletal muscle. Diabetes. 2006; 55:2077–83.
5. Ojuka EO, Jones TE, Han DH, Chen M, Wamhoff BR, Sturek M, et al. Intermittent increases in cytosolic Ca2+ stimulate mitochondrial biogenesis in muscle cells. Am J Physiol Endocrinol Metab. 2002; 283:E1040–5.
6. Rizzuto R, Brini M, Murgia M, Pozzan T. Microdomains with high Ca2+ close to IP3-sensitive channels that are sensed by neighboring mitochondria. Science. 1993; 262:744–7.
7. Trost SU, Belke DD, Bluhm WF, Meyer M, Swanson E, Dillmann WH. Overexpression of the sarcoplasmic reticulum Ca(2+)-ATPase improves myocardial contractility in diabetic cardiomyopathy. Diabetes. 2002; 51:1166–71.
Article
8. Paupe V, Prudent J. New insights into the role of mitochondrial calcium homeostasis in cell migration. Biochem Biophys Res Commun. 2018; 500:75–86.
Article
9. Ojuka EO, Jones TE, Han DH, Chen M, Holloszy JO. Raising Ca2+ in L6 myotubes mimics effects of exercise on mitochondrial biogenesis in muscle. FASEB J. 2003; 17:675–81.
10. Koh JH, Johnson ML, Dasari S, LeBrasseur NK, Vuckovic I, Henderson GC, et al. TFAM enhances fat oxidation and attenuates high-fat diet-induced insulin resistance in skeletal muscle. Diabetes. 2019; 68:1552–64.
Article
11. Nunnari J, Suomalainen A. Mitochondria: in sickness and in health. Cell. 2012; Mar. 16. 148:1145–59.
Article
12. Larsson NG, Barsh GS, Clayton DA. Structure and chromosomal localization of the mouse mitochondrial transcription factor A gene (Tfam). Mamm Genome. 1997; 8:139–40.
Article
13. Scarpulla RC. Transcriptional paradigms in mammalian mitochondrial biogenesis and function. Physiol Rev. 2008; 88:611–38.
Article
14. Kang I, Chu CT, Kaufman BA. The mitochondrial transcription factor TFAM in neurodegeneration: emerging evidence and mechanisms. FEBS Lett. 2018; 592:793–811.
Article
15. Fisher RP, Lisowsky T, Parisi MA, Clayton DA. DNA wrapping and bending by a mitochondrial high mobility group-like transcriptional activator protein. J Biol Chem. 1992; 267:3358–67.
Article
16. Fisher RP, Parisi MA, Clayton DA. Flexible recognition of rapidly evolving promoter sequences by mitochondrial transcription factor 1. Genes Dev. 1989; 3(12B):2202–17.
Article
17. Larsson NG, Wang J, Wilhelmsson H, Oldfors A, Rustin P, Lewandoski M, et al. Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice. Nat Genet. 1998; 18:231–6.
18. Ekstrand MI, Falkenberg M, Rantanen A, Park CB, Gaspari M, Hultenby K, et al. Mitochondrial transcription factor A regulates mtDNA copy number in mammals. Hum Mol Genet. 2004; 13:935–44.
Article
19. Whelan SP, Zuckerbraun BS. Mitochondrial signaling: forwards, backwards, and in between. Oxid Med Cell Longev. 2013; 2013:351613.
Article
20. Chau CM, Evans MJ, Scarpulla RC. Nuclear respiratory factor 1 activation sites in genes encoding the gamma-subunit of ATP synthase, eukaryotic initiation factor 2 alpha, and tyrosine aminotransferase. Specific interaction of purified NRF-1 with multiple target genes. J Biol Chem. 1992; 267:6999–7006.
Article
21. Virbasius JV, Scarpulla RC. Activation of the human mitochondrial transcription factor A gene by nuclear respiratory factors: a potential regulatory link between nuclear and mitochondrial gene expression in organelle biogenesis. Proc Natl Acad Sci U S A. 1994; 91:1309–13.
Article
22. Baar K, Wende AR, Jones TE, Marison M, Nolte LA, Chen M, et al. Adaptations of skeletal muscle to exercise: rapid increase in the transcriptional coactivator PGC-1. FASEB J. 2002; 16:1879–86.
Article
23. Murakami T, Shimomura Y, Yoshimura A, Sokabe M, Fujitsuka N. Induction of nuclear respiratory factor-1 expression by an acute bout of exercise in rat muscle. Biochim Biophys Acta. 1998; 1381:113–22.
Article
24. Piantadosi CA, Suliman HB. Mitochondrial transcription factor A induction by redox activation of nuclear respiratory factor 1. J Biol Chem. 2006; 281:324–33.
Article
25. Miranda S, Foncea R, Guerrero J, Leighton F. Oxidative stress and upregulation of mitochondrial biogenesis genes in mitochondrial DNA-depleted HeLa cells. Biochem Biophys Res Commun. 1999; 258:44–9.
Article
26. Suliman HB, Carraway MS, Welty-Wolf KE, Whorton AR, Piantadosi CA. Lipopolysaccharide stimulates mitochondrial biogenesis via activation of nuclear respiratory factor-1. J Biol Chem. 2003; 278:41510–8.
Article
27. Giorgi C, Agnoletto C, Bononi A, Bonora M, De Marchi E, Marchi S, et al. Mitochondrial calcium homeostasis as potential target for mitochondrial medicine. Mitochondrion. 2012; 12:77–85.
Article
28. Denton RM, McCormack JG. On the role of the calcium transport cycle in heart and other mammalian mitochondria. FEBS Lett. 1980; 119:1–8.
Article
29. Hansford RG, Castro F. Effects of micromolar concentrations of free calcium ions on the reduction of heart mitochondrial NAD(P) by 2-oxoglutarate. Biochem J. 1981; 198:525–33.
30. Murgia M, Rizzuto R. Molecular diversity and pleiotropic role of the mitochondrial calcium uniporter. Cell Calcium. 2015; 58:11–7.
Article
31. Ainbinder A, Boncompagni S, Protasi F, Dirksen RT. Role of mitofusin-2 in mitochondrial localization and calcium uptake in skeletal muscle. Cell Calcium. 2015; 57:14–24.
Article
32. Fujiwara Y, Kawaguchi Y, Fujimoto T, Kanayama N, Magari M, Tokumitsu H. Differential AMP-activated protein kinase (AMPK) recognition mechanism of Ca2+/calmodulin-dependent protein kinase kinase isoforms. J Biol Chem. 2016; 291:13802–8.
Article
33. Yuzefovych LV, LeDoux SP, Wilson GL, Rachek LI. Mitochondrial DNA damage via augmented oxidative stress regulates endoplasmic reticulum stress and autophagy: crosstalk, links and signaling. PLoS One. 2013; 8:e83349.
Article
34. Berridge MJ, Lipp P, Bootman MD. The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol. 2000; 1:11–21.
Article
35. Raffaello A, Mammucari C, Gherardi G, Rizzuto R. Calcium at the center of cell signaling: interplay between endoplasmic reticulum, mitochondria, and lysosomes. Trends Biochem Sci. 2016; 41:1035–49.
Article
36. Rizzuto R, Pinton P, Carrington W, Fay FS, Fogarty KE, Lifshitz LM, et al. Close contacts with the endoplasmic reticulum as determinants of mitochondrial Ca2+ responses. Science. 1998; 280:1763–6.
37. Bach D, Naon D, Pich S, Soriano FX, Vega N, Rieusset J, et al. Expression of Mfn2, the Charcot-Marie-Tooth neuropathy type 2A gene, in human skeletal muscle: effects of type 2 diabetes, obesity, weight loss, and the regulatory role of tumor necrosis factor alpha and interleukin-6. Diabetes. 2005; 54:2685–93.
38. Sebastian D, Hernandez-Alvarez MI, Segales J, Sorianello E, Munoz JP, Sala D, et al. Mitofusin 2 (Mfn2) links mitochondrial and endoplasmic reticulum function with insulin signaling and is essential for normal glucose homeostasis. Proc Natl Acad Sci U S A. 2012; 109:5523–8.
Article
39. De Stefani D, Bononi A, Romagnoli A, Messina A, De Pinto V, Pinton P, et al. VDAC1 selectively transfers apoptotic Ca2+ signals to mitochondria. Cell Death Differ. 2012; 19:267–73.
Article
40. Baughman JM, Perocchi F, Girgis HS, Plovanich M, BelcherTimme CA, Sancak Y, et al. Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature. 2011; 476:341–5.
Article
41. De Stefani D, Raffaello A, Teardo E, Szabo I, Rizzuto R. A fortykilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature. 2011; 476:336–40.
Article
42. Xu L, Wu Z, He Y, Chen Z, Xu K, Yu W, et al. MFN2 contributes to metabolic disorders and inflammation in the aging of rat chondrocytes and osteoarthritis. Osteoarthritis Cartilage. 2020; 28:1079–91.
Article
43. Mitchell P, Moyle J. Chemiosmotic hypothesis of oxidative phosphorylation. Nature. 1967; 213:137–9.
Article
44. Amuthan G, Biswas G, Ananadatheerthavarada HK, Vijayasarathy C, Shephard HM, Avadhani NG. Mitochondrial stressinduced calcium signaling, phenotypic changes and invasive behavior in human lung carcinoma A549 cells. Oncogene. 2002; 21:7839–49.
Article
45. Biswas G, Adebanjo OA, Freedman BD, Anandatheerthavarada HK, Vijayasarathy C, Zaidi M, et al. Retrograde Ca2+ signaling in C2C12 skeletal myocytes in response to mitochondrial genetic and metabolic stress: a novel mode of inter-organelle crosstalk. EMBO J. 1999; 18:522–33.
Article
46. Watanabe A, Arai M, Koitabashi N, Niwano K, Ohyama Y, Yamada Y, et al. Mitochondrial transcription factors TFAM and TFB2M regulate Serca2 gene transcription. Cardiovasc Res. 2011; 90:57–67.
Article
47. Aydin J, Andersson DC, Hanninen SL, Wredenberg A, Tavi P, Park CB, et al. Increased mitochondrial Ca2+ and decreased sarcoplasmic reticulum Ca2+ in mitochondrial myopathy. Hum Mol Genet. 2009; 18:278–88.
48. Cutler MJ, Wan X, Plummer BN, Liu H, Deschenes I, Laurita KR, et al. Targeted sarcoplasmic reticulum Ca2+ ATPase 2a gene delivery to restore electrical stability in the failing heart. Circulation. 2012; 126:2095–104.
49. Sommakia S, Houlihan PR, Deane SS, Simcox JA, Torres NS, Jeong MY, et al. Mitochondrial cardiomyopathies feature increased uptake and diminished efflux of mitochondrial calcium. J Mol Cell Cardiol. 2017; 113:22–32.
Article
50. Kirichok Y, Krapivinsky G, Clapham DE. The mitochondrial calcium uniporter is a highly selective ion channel. Nature. 2004; 427:360–4.
Article
51. Samanta K, Mirams GR, Parekh AB. Sequential forward and reverse transport of the Na+ Ca2+ exchanger generates Ca2+ oscillations within mitochondria. Nat Commun. 2018; 9:156.
Article
52. Jornayvaz FR, Shulman GI. Regulation of mitochondrial biogenesis. Essays Biochem. 2010; 47:69–84.
Article
53. Poyton RO, McEwen JE. Crosstalk between nuclear and mitochondrial genomes. Annu Rev Biochem. 1996; 65:563–607.
Article
54. Fischer C, DeFalco TA, Karia P, Snedden WA, Moeder W, Yoshioka K, et al. Calmodulin as a Ca2+-sensing subunit of Arabidopsis cyclic nucleotide-gated channel complexes. Plant Cell Physiol. 2017; 58:1208–21.
Article
55. Rose AJ, Kiens B, Richter EA. Ca2+-calmodulin-dependent protein kinase expression and signalling in skeletal muscle during exercise. J Physiol. 2006; 574(Pt 3):889–903.
Article
56. Jager S, Handschin C, St-Pierre J, Spiegelman BM. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc Natl Acad Sci U S A. 2007; 104:12017–22.
57. Koh JH, Hancock CR, Han DH, Holloszy JO, Nair KS, Dasari S. AMPK and PPARβ positive feedback loop regulates endurance exercise training-mediated GLUT4 expression in skeletal muscle. Am J Physiol Endocrinol Metab. 2019; 316:E931–9.
Article
58. Rowland AA, Voeltz GK. Endoplasmic reticulum-mitochondria contacts: function of the junction. Nat Rev Mol Cell Biol. 2012; 13:607–25.
Article
59. Yang C, Watson RT, Elmendorf JS, Sacks DB, Pessin JE. Calmodulin antagonists inhibit insulin-stimulated GLUT4 (glucose transporter 4) translocation by preventing the formation of phosphatidylinositol 3,4,5-trisphosphate in 3T3L1 adipocytes. Mol Endocrinol. 2000; 14:317–26.
Article
60. Contreras-Ferrat AE, Toro B, Bravo R, Parra V, Vasquez C, Ibarra C, et al. An inositol 1,4,5-triphosphate (IP3)-IP3 receptor pathway is required for insulin-stimulated glucose transporter 4 translocation and glucose uptake in cardiomyocytes. Endocrinology. 2010; 151:4665–77.
Article
61. Vial G, Dubouchaud H, Couturier K, Cottet-Rousselle C, Taleux N, Athias A, et al. Effects of a high-fat diet on energy metabolism and ROS production in rat liver. J Hepatol. 2011; 54:348–56.
Article
62. Fu S, Yang L, Li P, Hofmann O, Dicker L, Hide W, et al. Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity. Nature. 2011; 473:528–31.
Article
63. Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science. 2004; 306:457–61.
Article
64. Tubbs E, Theurey P, Vial G, Bendridi N, Bravard A, Chauvin MA, et al. Mitochondria-associated endoplasmic reticulum membrane (MAM) integrity is required for insulin signaling and is implicated in hepatic insulin resistance. Diabetes. 2014; 63:3279–94.
Article
65. Marchi S, Marinello M, Bononi A, Bonora M, Giorgi C, Rimessi A, et al. Selective modulation of subtype III IP₃R by Akt regulates ER Ca²+ release and apoptosis. Cell Death Dis. 2012; 3:e304.
66. Szado T, Vanderheyden V, Parys JB, De Smedt H, Rietdorf K, Kotelevets L, et al. Phosphorylation of inositol 1,4,5-trisphosphate receptors by protein kinase B/Akt inhibits Ca2+ release and apoptosis. Proc Natl Acad Sci U S A. 2008; 105:2427–32.
Article
67. Murley A, Lackner LL, Osman C, West M, Voeltz GK, Walter P, et al. ER-associated mitochondrial division links the distribution of mitochondria and mitochondrial DNA in yeast. Elife. 2013; 2:e00422.
Article
68. Lewis SC, Uchiyama LF, Nunnari J. ER-mitochondria contacts couple mtDNA synthesis with mitochondrial division in human cells. Science. 2016; 353:aaf5549.
Article
69. Chen H, Vermulst M, Wang YE, Chomyn A, Prolla TA, McCaffery JM, et al. Mitochondrial fusion is required for mtDNA stability in skeletal muscle and tolerance of mtDNA mutations. Cell. 2010; 141:280–9.
Article
70. Gan KX, Wang C, Chen JH, Zhu CJ, Song GY. Mitofusin-2 ameliorates high-fat diet-induced insulin resistance in liver of rats. World J Gastroenterol. 2013; 19:1572–81.
Article
71. Chitra L, Boopathy R. Altered mitochondrial biogenesis and its fusion gene expression is involved in the high-altitude adaptation of rat lung. Respir Physiol Neurobiol. 2014; 192:74–84.
Article
72. Alam TI, Kanki T, Muta T, Ukaji K, Abe Y, Nakayama H, et al. Human mitochondrial DNA is packaged with TFAM. Nucleic Acids Res. 2003; 31:1640–5.
Article
73. Kaufman BA, Durisic N, Mativetsky JM, Costantino S, Hancock MA, Grutter P, et al. The mitochondrial transcription factor TFAM coordinates the assembly of multiple DNA molecules into nucleoid-like structures. Mol Biol Cell. 2007; 18:3225–36.
Article
74. Ngo HB, Kaiser JT, Chan DC. The mitochondrial transcription and packaging factor Tfam imposes a U-turn on mitochondrial DNA. Nat Struct Mol Biol. 2011; 18:1290–6.
Article
75. Belke DD, Swanson E, Suarez J, Scott BT, Stenbit AE, Dillmann WH. Increased expression of SERCA in the hearts of transgenic mice results in increased oxidation of glucose. Am J Physiol Heart Circ Physiol. 2007; 292:H1755–63.
Article
76. Suarez J, Scott B, Dillmann WH. Conditional increase in SERCA2a protein is able to reverse contractile dysfunction and abnormal calcium flux in established diabetic cardiomyopathy. Am J Physiol Regul Integr Comp Physiol. 2008; 295:R1439–45.
Article
77. Kunkel GH, Chaturvedi P, Tyagi SC. Mitochondrial pathways to cardiac recovery: TFAM. Heart Fail Rev. 2016; 21:499–517.
Article
78. Neeb ZP, Edwards JM, Alloosh M, Long X, Mokelke EA, Sturek M. Metabolic syndrome and coronary artery disease in Ossabaw compared with Yucatan swine. Comp Med. 2010; 60:300–15.
79. Perocchi F, Gohil VM, Girgis HS, Bao XR, McCombs JE, Palmer AE, et al. MICU1 encodes a mitochondrial EF hand protein required for Ca(2+) uptake. Nature. 2010; 467:291–6.
Article
80. Plovanich M, Bogorad RL, Sancak Y, Kamer KJ, Strittmatter L, Li AA, et al. MICU2, a paralog of MICU1, resides within the mitochondrial uniporter complex to regulate calcium handling. PLoS One. 2013; 8:e55785.
Article
81. Raffaello A, De Stefani D, Sabbadin D, Teardo E, Merli G, Picard A, et al. The mitochondrial calcium uniporter is a multimer that can include a dominant-negative pore-forming subunit. EMBO J. 2013; 32:2362–76.
Article
82. Sancak Y, Markhard AL, Kitami T, Kovacs-Bogdan E, Kamer KJ, Udeshi ND, et al. EMRE is an essential component of the mitochondrial calcium uniporter complex. Science. 2013; 342:1379–82.
Article
83. Vecellio Reane D, Vallese F, Checchetto V, Acquasaliente L, Butera G, De Filippis V, et al. A MICU1 splice variant confers high sensitivity to the mitochondrial Ca2+ uptake machinery of skeletal muscle. Mol Cell. 2016; 64:760–73.
84. Pan X, Liu J, Nguyen T, Liu C, Sun J, Teng Y, et al. The physiological role of mitochondrial calcium revealed by mice lacking the mitochondrial calcium uniporter. Nat Cell Biol. 2013; 15:1464–72.
Article
85. Gherardi G, Nogara L, Ciciliot S, Fadini GP, Blaauw B, Braghetta P, et al. Loss of mitochondrial calcium uniporter rewires skeletal muscle metabolism and substrate preference. Cell Death Differ. 2019; 26:362–81.
Article
86. Koves TR, Ussher JR, Noland RC, Slentz D, Mosedale M, Ilkayeva O, et al. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab. 2008; 7:45–56.
Article
87. Hattori Y, Matsuda N, Kimura J, Ishitani T, Tamada A, Gando S, et al. Diminished function and expression of the cardiac Na+- Ca2+ exchanger in diabetic rats: implication in Ca2+ overload. J Physiol. 2000; 527(Pt 1):85–94.
88. Kashihara H, Shi ZQ, Yu JZ, McNeill JH, Tibbits GF. Effects of diabetes and hypertension on myocardial Na+-Ca2+ exchange. Can J Physiol Pharmacol. 2000; 78:12–9.
Article
89. Draznin B, Sussman KE, Eckel RH, Kao M, Yost T, Sherman NA. Possible role of cytosolic free calcium concentrations in mediating insulin resistance of obesity and hyperinsulinemia. J Clin Invest. 1988; 82:1848–52.
Article
90. Draznin B, Lewis D, Houlder N, Sherman N, Adamo M, Garvey WT, et al. Mechanism of insulin resistance induced by sustained levels of cytosolic free calcium in rat adipocytes. Endocrinology. 1989; 125:2341–9.
Article
91. Barros MH, Bandy B, Tahara EB, Kowaltowski AJ. Higher respiratory activity decreases mitochondrial reactive oxygen release and increases life span in Saccharomyces cerevisiae. J Biol Chem. 2004; 279:49883–8.
Article
92. Davidson JF, Schiestl RH. Mitochondrial respiratory electron carriers are involved in oxidative stress during heat stress in Saccharomyces cerevisiae. Mol Cell Biol. 2001; 21:8483–9.
93. Gourlay CW, Carpp LN, Timpson P, Winder SJ, Ayscough KR. A role for the actin cytoskeleton in cell death and aging in yeast. J Cell Biol. 2004; 164:803–9.
Article
94. Barrientos A, Moraes CT. Simultaneous transfer of mitochondrial DNA and single chromosomes in somatic cells: a novel approach for the study of defects in nuclear-mitochondrial communication. Hum Mol Genet. 1998; 7:1801–8.
Article
95. Mastromonaco GF, Favetta LA, Smith LC, Filion F, King WA. The influence of nuclear content on developmental competence of gaur x cattle hybrid in vitro fertilized and somatic cell nuclear transfer embryos. Biol Reprod. 2007; 76:514–23.
Full Text Links
  • DMJ
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr