Mitochondrial biogenesis and remodeling occur in response to exercise and redox state (reviewed in Scarpulla et al. 2012, Handy and Loscalzo 2012, Piantadosi and Suliman 2012, Scarpulla 2011, Wenz et al. 2011, Bo et al. 2010, Jornayvaz and Shulman 2010, Ljubicic et al. 2010, Hock and Kralli 2009, Canto and Auwerx 2009, Lin 2009, Scarpulla 2008, Ventura-Clapier et al. 2008). It is hypothesized that calcium influx and energy depletion are the signals that initiate changes in gene expression leading to new mitochondrial proteins. Energy depletion causes a reduction in ATP and an increase in AMP which activates AMPK. AMPK in turn phosphorylates the coactivator PGC-1alpha (PPARGC1A), one of the master regulators of mitochondrial biosynthesis. Likewise, p38 MAPK is activated by muscle contraction (possibly via calcium and CaMKII) and phosphorylates PGC-1alpha. CaMKIV responds to intracellular calcium by phosphorylating CREB, which activates expression of PGC-1alpha. Deacetylation of PGC-1alpha by SIRT1 may also play a role in activation (Canto et al. 2009, Gurd et al. 2011), however Sirt11 deacetylation of Ppargc1a in mouse impacted genes related to glucose metabolism rather than mitochondrial biogenesis (Rodgers et al. 2005) and mice lacking SIRT1 in muscle had normal levels of mitochondrial biogenesis in response to exercise (Philp et al. 2011) so the role of deacetylation is not fully defined. PGC-1beta and PPRC appear to act similarly to PGC-1alpha but they have not been as well studied. Phosphorylated PGC-1alpha does not bind DNA directly but instead interacts with other transcription factors, notably NRF1 and NRF2 (via HCF1). NRF1 and NRF2 together with PGC-1alpha activate the transcription of nuclear-encoded, mitochondrially targeted proteins such as TFB2M, TFB1M, and TFAM.
View original pathway at Reactome.
Bo H, Zhang Y, Ji LL.; ''Redefining the role of mitochondria in exercise: a dynamic remodeling.''; PubMedEurope PMCScholia
Bruni F, Polosa PL, Gadaleta MN, Cantatore P, Roberti M.; ''Nuclear respiratory factor 2 induces the expression of many but not all human proteins acting in mitochondrial DNA transcription and replication.''; PubMedEurope PMCScholia
Seelert H, Dencher NA.; ''ATP synthase superassemblies in animals and plants: two or more are better.''; PubMedEurope PMCScholia
Knutti D, Kaul A, Kralli A.; ''A tissue-specific coactivator of steroid receptors, identified in a functional genetic screen.''; PubMedEurope PMCScholia
Shi H, Shigeta H, Yang N, Fu K, O'Brian G, Teng CT.; ''Human estrogen receptor-like 1 (ESRL1) gene: genomic organization, chromosomal localization, and promoter characterization.''; PubMedEurope PMCScholia
Gurd BJ, Yoshida Y, McFarlan JT, Holloway GP, Moyes CD, Heigenhauser GJ, Spriet L, Bonen A.; ''Nuclear SIRT1 activity, but not protein content, regulates mitochondrial biogenesis in rat and human skeletal muscle.''; PubMedEurope PMCScholia
Scarpulla RC, Vega RB, Kelly DP.; ''Transcriptional integration of mitochondrial biogenesis.''; PubMedEurope PMCScholia
Endo T, Yamano K.; ''Multiple pathways for mitochondrial protein traffic.''; PubMedEurope PMCScholia
Bonnelye E, Vanacker JM, Dittmar T, Begue A, Desbiens X, Denhardt DT, Aubin JE, Laudet V, Fournier B.; ''The ERR-1 orphan receptor is a transcriptional activator expressed during bone development.''; PubMedEurope PMCScholia
Michishita E, Park JY, Burneskis JM, Barrett JC, Horikawa I.; ''Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins.''; PubMedEurope PMCScholia
Cotney J, McKay SE, Shadel GS.; ''Elucidation of separate, but collaborative functions of the rRNA methyltransferase-related human mitochondrial transcription factors B1 and B2 in mitochondrial biogenesis reveals new insight into maternally inherited deafness.''; PubMedEurope PMCScholia
Piantadosi CA, Suliman HB.; ''Transcriptional control of mitochondrial biogenesis and its interface with inflammatory processes.''; PubMedEurope PMCScholia
Leyva JA, Bianchet MA, Amzel LM.; ''Understanding ATP synthesis: structure and mechanism of the F1-ATPase (Review).''; PubMedEurope PMCScholia
Cotney J, Shadel GS.; ''Evidence for an early gene duplication event in the evolution of the mitochondrial transcription factor B family and maintenance of rRNA methyltransferase activity in human mtTFB1 and mtTFB2.''; PubMedEurope PMCScholia
Larrouy D, Vidal H, Andreelli F, Laville M, Langin D.; ''Cloning and mRNA tissue distribution of human PPARgamma coactivator-1.''; PubMedEurope PMCScholia
Little JP, Safdar A, Safdar A, Bishop D, Tarnopolsky MA, Gibala MJ.; ''An acute bout of high-intensity interval training increases the nuclear abundance of PGC-1α and activates mitochondrial biogenesis in human skeletal muscle.''; PubMedEurope PMCScholia
Wenz T.; ''Mitochondria and PGC-1α in Aging and Age-Associated Diseases.''; PubMedEurope PMCScholia
Kienhöfer J, Häussler DJ, Ruckelshausen F, Muessig E, Weber K, Pimentel D, Ullrich V, Bürkle A, Bachschmid MM.; ''Association of mitochondrial antioxidant enzymes with mitochondrial DNA as integral nucleoid constituents.''; PubMedEurope PMCScholia
Juge-Aubry C, Pernin A, Favez T, Burger AG, Wahli W, Meier CA, Desvergne B.; ''DNA binding properties of peroxisome proliferator-activated receptor subtypes on various natural peroxisome proliferator response elements. Importance of the 5'-flanking region.''; PubMedEurope PMCScholia
Darshi M, Mendiola VL, Mackey MR, Murphy AN, Koller A, Perkins GA, Ellisman MH, Taylor SS.; ''ChChd3, an inner mitochondrial membrane protein, is essential for maintaining crista integrity and mitochondrial function.''; PubMedEurope PMCScholia
Kutik S, Guiard B, Meyer HE, Wiedemann N, Pfanner N.; ''Cooperation of translocase complexes in mitochondrial protein import.''; PubMedEurope PMCScholia
Vercauteren K, Gleyzer N, Scarpulla RC.; ''PGC-1-related coactivator complexes with HCF-1 and NRF-2beta in mediating NRF-2(GABP)-dependent respiratory gene expression.''; PubMedEurope PMCScholia
Scher MB, Vaquero A, Reinberg D.; ''SirT3 is a nuclear NAD+-dependent histone deacetylase that translocates to the mitochondria upon cellular stress.''; PubMedEurope PMCScholia
Handy DE, Loscalzo J.; ''Redox regulation of mitochondrial function.''; PubMedEurope PMCScholia
Gopalakrishnan L, Scarpulla RC.; ''Structure, expression, and chromosomal assignment of the human gene encoding nuclear respiratory factor 1.''; PubMedEurope PMCScholia
Wright DC, Han DH, Garcia-Roves PM, Geiger PC, Jones TE, Holloszy JO.; ''Exercise-induced mitochondrial biogenesis begins before the increase in muscle PGC-1alpha expression.''; PubMedEurope PMCScholia
Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM.; ''A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis.''; PubMedEurope PMCScholia
Blanco-Aparicio C, Torres J, Pulido R.; ''A novel regulatory mechanism of MAP kinases activation and nuclear translocation mediated by PKA and the PTP-SL tyrosine phosphatase.''; PubMedEurope PMCScholia
Pilegaard H, Saltin B, Neufer PD.; ''Exercise induces transient transcriptional activation of the PGC-1alpha gene in human skeletal muscle.''; PubMedEurope PMCScholia
Habersetzer J, Ziani W, Larrieu I, Stines-Chaumeil C, Giraud MF, Brèthes D, Dautant A, Paumard P.; ''ATP synthase oligomerization: from the enzyme models to the mitochondrial morphology.''; PubMedEurope PMCScholia
Jiang Y, Gram H, Zhao M, New L, Gu J, Feng L, Di Padova F, Ulevitch RJ, Han J.; ''Characterization of the structure and function of the fourth member of p38 group mitogen-activated protein kinases, p38delta.''; PubMedEurope PMCScholia
Ventura-Clapier R, Garnier A, Veksler V.; ''Transcriptional control of mitochondrial biogenesis: the central role of PGC-1alpha.''; PubMedEurope PMCScholia
Glytsou C, Calvo E, Cogliati S, Mehrotra A, Anastasia I, Rigoni G, Raimondi A, Shintani N, Loureiro M, Vazquez J, Pellegrini L, Enriquez JA, Scorrano L, Soriano ME.; ''Optic Atrophy 1 Is Epistatic to the Core MICOS Component MIC60 in Mitochondrial Cristae Shape Control.''; PubMedEurope PMCScholia
Onyango P, Celic I, McCaffery JM, Boeke JD, Feinberg AP.; ''SIRT3, a human SIR2 homologue, is an NAD-dependent deacetylase localized to mitochondria.''; PubMedEurope PMCScholia
Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V, Troy A, Cinti S, Lowell B, Scarpulla RC, Spiegelman BM.; ''Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1.''; PubMedEurope PMCScholia
Gleyzer N, Vercauteren K, Scarpulla RC.; ''Control of mitochondrial transcription specificity factors (TFB1M and TFB2M) by nuclear respiratory factors (NRF-1 and NRF-2) and PGC-1 family coactivators.''; PubMedEurope PMCScholia
Bolender N, Sickmann A, Wagner R, Meisinger C, Pfanner N.; ''Multiple pathways for sorting mitochondrial precursor proteins.''; PubMedEurope PMCScholia
Julliard JH, Smith EL.; ''Partial amino acid sequence of the glutamate dehydrogenase of human liver and a revision of the sequence of the bovine enzyme.''; PubMedEurope PMCScholia
Wu Z, Huang X, Feng Y, Handschin C, Feng Y, Gullicksen PS, Bare O, Labow M, Spiegelman B, Stevenson SC.; ''Transducer of regulated CREB-binding proteins (TORCs) induce PGC-1alpha transcription and mitochondrial biogenesis in muscle cells.''; PubMedEurope PMCScholia
van der Laan M, Rissler M, Rehling P.; ''Mitochondrial preprotein translocases as dynamic molecular machines.''; PubMedEurope PMCScholia
Kang Y, Fielden LF, Stojanovski D.; ''Mitochondrial protein transport in health and disease.''; PubMedEurope PMCScholia
Yamamoto H, Fukui K, Takahashi H, Kitamura S, Shiota T, Terao K, Uchida M, Esaki M, Nishikawa S, Yoshihisa T, Yamano K, Endo T.; ''Roles of Tom70 in import of presequence-containing mitochondrial proteins.''; PubMedEurope PMCScholia
Milenkovic D, Müller J, Stojanovski D, Pfanner N, Chacinska A.; ''Diverse mechanisms and machineries for import of mitochondrial proteins.''; PubMedEurope PMCScholia
Lin JD.; ''Minireview: the PGC-1 coactivator networks: chromatin-remodeling and mitochondrial energy metabolism.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Roberts AG, Elder GH.; ''Alternative splicing and tissue-specific transcription of human and rodent ubiquitous 5-aminolevulinate synthase (ALAS1) genes.''; PubMedEurope PMCScholia
Stojanovski D, Müller JM, Milenkovic D, Guiard B, Pfanner N, Chacinska A.; ''The MIA system for protein import into the mitochondrial intermembrane space.''; PubMedEurope PMCScholia
Gibala MJ, McGee SL, Garnham AP, Howlett KF, Snow RJ, Hargreaves M.; ''Brief intense interval exercise activates AMPK and p38 MAPK signaling and increases the expression of PGC-1alpha in human skeletal muscle.''; PubMedEurope PMCScholia
Schlicker C, Gertz M, Papatheodorou P, Kachholz B, Becker CF, Steegborn C.; ''Substrates and regulation mechanisms for the human mitochondrial sirtuins Sirt3 and Sirt5.''; PubMedEurope PMCScholia
Cantó C, Auwerx J.; ''PGC-1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure.''; PubMedEurope PMCScholia
Schwer B, North BJ, Frye RA, Ott M, Verdin E.; ''The human silent information regulator (Sir)2 homologue hSIRT3 is a mitochondrial nicotinamide adenine dinucleotide-dependent deacetylase.''; PubMedEurope PMCScholia
Luong A, Hannah VC, Brown MS, Goldstein JL.; ''Molecular characterization of human acetyl-CoA synthetase, an enzyme regulated by sterol regulatory element-binding proteins.''; PubMedEurope PMCScholia
Tominaga K, Hayashi J, Kagawa Y, Ohta S.; ''Smaller isoform of human mitochondrial transcription factor 1: its wide distribution and production by alternative splicing.''; PubMedEurope PMCScholia
Scarpulla RC.; ''Nuclear control of respiratory chain expression by nuclear respiratory factors and PGC-1-related coactivator.''; PubMedEurope PMCScholia
Izquierdo JM.; ''Control of the ATP synthase beta subunit expression by RNA-binding proteins TIA-1, TIAR, and HuR.''; PubMedEurope PMCScholia
Ljubicic V, Joseph AM, Saleem A, Uguccioni G, Collu-Marchese M, Lai RY, Nguyen LM, Hood DA.; ''Transcriptional and post-transcriptional regulation of mitochondrial biogenesis in skeletal muscle: effects of exercise and aging.''; PubMedEurope PMCScholia
van der Laan M, Hutu DP, Rehling P.; ''On the mechanism of preprotein import by the mitochondrial presequence translocase.''; PubMedEurope PMCScholia
Ahuja N, Schwer B, Carobbio S, Waltregny D, North BJ, Castronovo V, Maechler P, Verdin E.; ''Regulation of insulin secretion by SIRT4, a mitochondrial ADP-ribosyltransferase.''; PubMedEurope PMCScholia
van der Laan M, Horvath SE, Pfanner N.; ''Mitochondrial contact site and cristae organizing system.''; PubMedEurope PMCScholia
Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P.; ''Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1.''; PubMedEurope PMCScholia
Schwer B, Bunkenborg J, Verdin RO, Andersen JS, Verdin E.; ''Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2.''; PubMedEurope PMCScholia
Scarpulla RC.; ''Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network.''; PubMedEurope PMCScholia
Jackson MD, Denu JM.; ''Structural identification of 2'- and 3'-O-acetyl-ADP-ribose as novel metabolites derived from the Sir2 family of beta -NAD+-dependent histone/protein deacetylases.''; PubMedEurope PMCScholia
Zick M, Rabl R, Reichert AS.; ''Cristae formation-linking ultrastructure and function of mitochondria.''; PubMedEurope PMCScholia
Wiedemann N, Pfanner N.; ''Mitochondrial Machineries for Protein Import and Assembly.''; PubMedEurope PMCScholia
Kravchenko JE, Rogozin IB, Koonin EV, Chumakov PM.; ''Transcription of mammalian messenger RNAs by a nuclear RNA polymerase of mitochondrial origin.''; PubMedEurope PMCScholia
Philp A, Chen A, Lan D, Meyer GA, Murphy AN, Knapp AE, Olfert IM, McCurdy CE, Marcotte GR, Hogan MC, Baar K, Schenk S.; ''Sirtuin 1 (SIRT1) deacetylase activity is not required for mitochondrial biogenesis or peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) deacetylation following endurance exercise.''; PubMedEurope PMCScholia
Cantó C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC, Elliott PJ, Puigserver P, Auwerx J.; ''AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity.''; PubMedEurope PMCScholia
Andersson U, Scarpulla RC.; ''Pgc-1-related coactivator, a novel, serum-inducible coactivator of nuclear respiratory factor 1-dependent transcription in mammalian cells.''; PubMedEurope PMCScholia
Vercauteren K, Pasko RA, Gleyzer N, Marino VM, Scarpulla RC.; ''PGC-1-related coactivator: immediate early expression and characterization of a CREB/NRF-1 binding domain associated with cytochrome c promoter occupancy and respiratory growth.''; PubMedEurope PMCScholia
Rampelt H, Zerbes RM, van der Laan M, Pfanner N.; ''Role of the mitochondrial contact site and cristae organizing system in membrane architecture and dynamics.''; PubMedEurope PMCScholia
Sideris DP, Tokatlidis K.; ''Oxidative protein folding in the mitochondrial intermembrane space.''; PubMedEurope PMCScholia
Bilbao A, Parkitna JR, Engblom D, Perreau-Lenz S, Sanchis-Segura C, Schneider M, Konopka W, Westphal M, Breen G, Desrivieres S, Klugmann M, Guindalini C, Vallada H, Laranjeira R, de Fonseca FR, Schumann G, Schütz G, Spanagel R.; ''Loss of the Ca2+/calmodulin-dependent protein kinase type IV in dopaminoceptive neurons enhances behavioral effects of cocaine.''; PubMedEurope PMCScholia
Gugneja S, Virbasius JV, Scarpulla RC.; ''Four structurally distinct, non-DNA-binding subunits of human nuclear respiratory factor 2 share a conserved transcriptional activation domain.''; PubMedEurope PMCScholia
Deponte M, Hell K.; ''Disulphide bond formation in the intermembrane space of mitochondria.''; PubMedEurope PMCScholia
Jornayvaz FR, Shulman GI.; ''Regulation of mitochondrial biogenesis.''; PubMedEurope PMCScholia
Lombard DB, Alt FW, Cheng HL, Bunkenborg J, Streeper RS, Mostoslavsky R, Kim J, Yancopoulos G, Valenzuela D, Murphy A, Yang Y, Chen Y, Hirschey MD, Bronson RT, Haigis M, Guarente LP, Farese RV, Weissman S, Verdin E, Schwer B.; ''Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation.''; PubMedEurope PMCScholia
Zheng J, Shan Y, Lambrecht RW, Donohue SE, Bonkovsky HL.; ''Differential regulation of human ALAS1 mRNA and protein levels by heme and cobalt protoporphyrin.''; PubMedEurope PMCScholia
Cooper HM, Spelbrink JN.; ''The human SIRT3 protein deacetylase is exclusively mitochondrial.''; PubMedEurope PMCScholia
Hock MB, Kralli A.; ''Transcriptional control of mitochondrial biogenesis and function.''; PubMedEurope PMCScholia
McCulloch V, Seidel-Rogol BL, Shadel GS.; ''A human mitochondrial transcription factor is related to RNA adenine methyltransferases and binds S-adenosylmethionine.''; PubMedEurope PMCScholia
Knutti D, Kressler D, Kralli A.; ''Regulation of the transcriptional coactivator PGC-1 via MAPK-sensitive interaction with a repressor.''; PubMedEurope PMCScholia
Metodiev MD, Lesko N, Park CB, Cámara Y, Shi Y, Wibom R, Hultenby K, Gustafsson CM, Larsson NG.; ''Methylation of 12S rRNA is necessary for in vivo stability of the small subunit of the mammalian mitochondrial ribosome.''; PubMedEurope PMCScholia
Cristae are invaginations of the inner mitochondrial membrane that extend into the matrix and are lined with cytochrome complexes and F1Fo ATP synthase complexes. Cristae increase the surface area of the inner membranes allowing greater numbers of respiratory complexes. Cristae are also believed to serve as "proton pockets" to generate localized regions of higher membrane potential. The steps in the biogenesis of cristae are not yet completely elucidated (reviewed in Zick et al. 2009) but the formation of the Mitochondrial Contact Site and Cristae Organizing System (MICOS, formerly also known as MINOS, reviewed in Rampelt et al. 2016, Kozjak-Pavlovic 2016, van der Laan et al. 2016) and localized concentrations of cardiolipin are known to define the inward curvature of the inner membrane at the bases of cristae. MICOS also links these regions of the inner membrane with complexes (the SAM complex and, in fungi, the TOM complex) embedded in the outer membrane. CHCHD3 (MIC19) and IMMT (MIC60) subunits of MICOS also interact with OPA1 at the inner membrane (Darshi et al. 2011, Glytsou et al. 2016). Formation of dimers or oligomers of the F1Fo ATP synthase complex causes extreme curvature of the inner membrane at the apices of cristae (reviewed in Seelert and Dencher 2011, Habersetzer et al. 2013). Defects in either MICOS or F1Fo ATP synthase oligomerization produce abnormal mitochondrial morphologies.
MED1 is a component of each of the various Mediator complexes, that function as transcription co-activators. The MED1-containing compolexes include the DRIP, ARC, TRIP and CRSP compllexes.
A human mitochondrion contains about 1500 proteins, more than 99% of which are encoded in the nucleus, synthesized in the cytosol and imported into the mitochondrion. Proteins are targeted to four locations (outer membrane, intermembrane space, inner membrane, and matrix) and must be sorted accordingly (reviewed in Kutik et al. 2007, Milenkovic et al. 2007, Bolender et al. 2008, Endo and Yamano 2009, Wiedemann and Pfanner 2017, Kang et al. 2018). Newly synthesized proteins are transported from the cytosol across the outer membrane by the TOMM40:TOMM70 complex. Proteins that contain presequences first interact with the TOMM20 subunit of the complex while proteins that contain internal targeting elements first interact with the TOMM70 subunit. After initial interaction the protein is conducted across the outer membrane by TOMM40 subunits. In yeast some proteins such as Aco1, Atp1, Cit1, Idh1, and Atp2 have both presequences that interact with TOM20 and mature regions that interact with TOM70 (Yamamoto et al. 2009). After passage across the outer membrane, proteins may be targeted to the outer membrane via the SAMM50 complex, to the inner membrane via the TIMM22 or TIMM23 complexes (reviewed in van der Laan et al. 2010), to the matrix via the TIMM23 complex (reviewed in van der Laan et al. 2010), or proteins may fold and remain in the intermembrane space (reviewed in Stojanovski et al. 2008, Deponte and Hell 2009, Sideris and Tokatlidis 2010). Presequences on matrix and inner membrane proteins cause interaction with TIMM23 complexes; internal targeting sequences cause outer membrane proteins to interact with the SAMM50 complex and inner membrane proteins to interact with the TIMM22 complex. While in the intermembrane space hydrophobic proteins are chaperoned by the TIMM8:TIMM13 complex and/or the TIMM9:TIMM10:FXC1 complex.
Peroxisome proliferator receptor elements bind heterodimers containing a peroxisome proliferator receptor and a retinoic acid receptor. The consensus sequence is TGAMCTTTGNCCTAGWTYYG.
The cAMP-responsive element binding protein (CREB), a key regulator of gene expression, is activated by phosphorylation on Ser-133. Several different protein kinases possess the capability of driving this phosphorylation, making it a point of convergence for multiple intracellular signaling cascades. Work in neurons has indicated that physiologic synaptic stimulation recruits a fast calmodulin kinase IV (CaMKIV)-dependent pathway that dominates early signaling to CREB. Activated CaMKIV (CAMK4) phosphorylates CREB1 at S133, thereby initiating the transcription of CREB1-regulated set of genes, leading to protein synthesis and long lasting changes that underlie synaptic plasticity.
The PPARGC1A (PGC-1alpha) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. PPARGC1A protein is located in the nucleus where it coactivates transcription.
TFAM is encoded in the nucleus, synthesized as a precursor in the cytosol, and imported into the mitochondrial matrix (presumably by the SAM50 complex and the TIM23:PAM complex, reviewed in van der Laan et al. 2006). In the mitochondrial matrix TFAM binds the light strand promoter of mitochondrial DNA and regulates transcription.
The gene encoding cytochrome c (CYCS) is transcribed in the nucleus to yield mRNA and the mRNA is translated in the cytosol to yield the precursor of cytochrome c, which is then imported into the mitochodrial matrix and associates with the matrix face of the inner membrane.
The TFB1M gene is transcribed to yield mRNA and the mRNA is translated to yield precursor protein in the cytosol (McCulloch et al. 2002, Gleyzer et al. 2005, Vercauteren et al. 2008, Cotney et al. 2009). The TFB1M precursor is then imported into the mitochondiral matrix where it acts as both a 12S RNA methylase and a DNA-binding transcription factor (inferred from mouse in Metodiev et al. 2009).
As inferred from mouse, p38 MAPK phosphorylates PGC-1alpha (PPARGC1A). Because p38 MAPK is responsive to intracellular calcium, this reaction may couple exercise to mitochondrial biogenesis. Phosphorylated p38 MAPK is found in the nucleus (Chan et al. 2004, http://www.cellsignal.com/products/4511.html, inferred from mouse in Blanco-Aparicio et al. 1999). p38 MAPK alpha, beta, and gamma (but not delta) are found in skeletal muscle (Jiang et al. 1997). PPARGC1A (PGC-1alpha) is predominantly nuclear (Knutti et al. 2001). As inferred from rat, PPARGC1A may translocate from the cytosol to the nucleus during activation (Wright et al. 2007).
The GABPA (NRF2 alpha subunit) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Two subunits of GABPA bind two subunits of GABPB1 to form Nuclear respiratory factor 2 (NRF2).
The POLG2 gene is transcribed to yield mRNA and the mRNA is translated in the cytosol to yield precursor protein.POLG2 is imported into the mitochondrial matrix where it functions in DNA replication.
PGC-1alpha (PPARGC1A) binds NRF1 and coactivates genes regulated by NRF1 (Gleyzer et al. 2005, Vercauteren et al. 2008, inferred from mouse in Wu et al. 1999).
The ALAS1 gene is transcribed to yield mRNA and the mRNA is translated in the cytosol to yield precursor protein. The ALAS1 precursor is imported into the mitochodrial matrix where it catalyzes the synthesis of 5-aminolevulinate from glycine and succinyl-CoA as part of heme biosynthesis.
The PEO1 (TWINKLE) gene is transcribed to yield mRNA and the mRNA is translated in the cytosol to yield precursor protein. PEO1 is imported into the mitochondrial matrix where it may play a role in DNA replication.
The SSBP1 (mtSSB) gene is transcribed in the nucleus to yield mRNA and the mRNA is translated in the cytosol to yield precursor protein. The precursor SSBP1 is imported into the mitochondiral matrix where it binds single-stranded DNA.
The NRF1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. NRF1 protein is located in the nucleus where it regulates transcription.
The POLRMT (mitochondrial RNA polymerase) gene is transcribed in the nucleus to yield mRNA and the mRNA is translated in the cytosol to yield POLRMT precursor, which is then imported into the mitochondria matrix. In the mitochondrial matrix POLRMT transcribes mitochondrial DNA.
As inferred from mouse, AMPK is activated by AMP and phosphorylates PGC-1alpha (PPARGC1A). It is hypothesized that this reaction connects energy depletion (low ATP, high AMP) to mitochondrial biogenesis (activation of PGC-1alpha).
The ATP5B (ATP synthase beta subunit) gene is transcribed in the nucleus to yield mRNA and the mRNA is translated in the cytosol to yield the ATP5B precursor, which is then imported into the mitochondrial matrix. ATP5B is a peripheral membrane protein located at the matrix face of the inner membrane within the ATP synthase complex (reviewed in Leyva et al. 2003).
The mTERF gene is transcribed in the nucleus to yield mRNA and the mRNA is translated in the cytosol to yield precursor protein. mTERF is imported into the mitochondrial matrix where it plays a role in terminating transcription.
The TFB2M gene is transcribed to yield mRNA and the mRNA is translated to yield protein. The TFB2M precursor is then imported into the mitochondiral matrix where it acts as both a 12S RNA methylase and a DNA-binding transcription factor (Gleyzer et al. 2005, Cotney and Shadel 2006, Vercauteren et al. 2008).
The ERR1 (ERRalpha) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. ERR1 is a nuclear receptor that interacts with PPARGC1A (PGC-1alpha) and regulates energy metabolism.
The SIRT3 gene is transcribed to yield mRNA and the mRNA is translated in the cytosol to yield precursor protein. SIRT3 is imported into the mitochondrial matrix where it deacetylates, and hence activates, target proteins
PGC-1alpha (PPARGC1A) binds NRF1 and coactivates genes regulated by NRF1 (Gleyzer et al. 2005, Vercauteren et al. 2008, inferred from mouse in Wu et al. 1999).
Sirtuin 4 (SIRT4) is a mitochondrial ADP-ribosyltransferase and deacetylase. It uses NAD+ to ADP-ribosylate glutamate dehydrogenase (GLUD), reducing its enzyme activity by at least 50%, leading to reduced insulin secretion in pancreatic beta cells (Haigis et al. 2006, Ahuja et al. 2007).
Sirtuin 3 (SIRT3) is the most extensively studied of the mitochondrial sirtuins. It deacetylates and thereby activates Acetyl-CoA synthetase 2 (ACCS2), Glutamate dehydrogenase (GLUD), Isocitrate dehydrogenase 2 (IDH2) and Superoxide dismutase 2 (SOD2) (Schwer et al. 2006, Lombard et al. 2007, Schlicker et al. 2008, Tao et al. 2010).
Sirtuin 5 has been shown to deacetylate Cytochrome C in the the mitochondrial intermembrane space (Schlicker et al. 2008). The functional significance of this is unknown (Bao & Sack 2010).
As inferred from the mouse homolog, the PERM1 gene is transcribed to yield mRNA, the mRNA is translated to yield protein. The PERM1 gene is expressed selectively in muscle where it is activated by PPARGC1A via the estrogen receptor ESRRA, which binds regulatory regions of the PERM1 gene. PERM1 selectively regulates mitochondrial biogenesis and oxidative function.
Try the New WikiPathways
View approved pathways at the new wikipathways.org.Quality Tags
Ontology Terms
Bibliography
History
External references
DataNodes
Formation of dimers or oligomers of the F1Fo ATP synthase complex causes extreme curvature of the inner membrane at the apices of cristae (reviewed in Seelert and Dencher 2011, Habersetzer et al. 2013). Defects in either MICOS or F1Fo ATP synthase oligomerization produce abnormal mitochondrial morphologies.
After passage across the outer membrane, proteins may be targeted to the outer membrane via the SAMM50 complex, to the inner membrane via the TIMM22 or TIMM23 complexes (reviewed in van der Laan et al. 2010), to the matrix via the TIMM23 complex (reviewed in van der Laan et al. 2010), or proteins may fold and remain in the intermembrane space (reviewed in Stojanovski et al. 2008, Deponte and Hell 2009, Sideris and Tokatlidis 2010). Presequences on matrix and inner membrane proteins cause interaction with TIMM23 complexes; internal targeting sequences cause outer membrane proteins to interact with the SAMM50 complex and inner membrane proteins to interact with the TIMM22 complex. While in the intermembrane space hydrophobic proteins are chaperoned by the TIMM8:TIMM13 complex and/or the TIMM9:TIMM10:FXC1 complex.
alpha/beta/gamma
MAPKAnnotated Interactions
Phosphorylated p38 MAPK is found in the nucleus (Chan et al. 2004, http://www.cellsignal.com/products/4511.html, inferred from mouse in Blanco-Aparicio et al. 1999). p38 MAPK alpha, beta, and gamma (but not delta) are found in skeletal muscle (Jiang et al. 1997). PPARGC1A (PGC-1alpha) is predominantly nuclear (Knutti et al. 2001). As inferred from rat, PPARGC1A may translocate from the cytosol to the nucleus during activation (Wright et al. 2007).
alpha/beta/gamma
MAPK