Mitochondrial biogenesis

{{short description|Process by which cells build mitochondrial mass}}

Mitochondrial biogenesis is the process by which cells increase mitochondrial numbers.{{cite journal |doi=10.2174/138161282035140911142118 |pmid=24606795 |title=Editorial (Thematic Issue: Mitochondrial Biogenesis: Pharmacological Approaches) |journal=Current Pharmaceutical Design |volume=20 |issue=35 |pages=5507–5509 |year=2014 |last1=Valero |first1=Teresa | name-list-style = vanc |hdl=10454/13341 |hdl-access=free }}{{cite journal | vauthors = Sanchis-Gomar F, García-Giménez JL, Gómez-Cabrera MC, Pallardó FV | title = Mitochondrial biogenesis in health and disease. Molecular and therapeutic approaches | journal = Current Pharmaceutical Design | volume = 20 | issue = 35 | pages = 5619–33 | year = 2014 | pmid = 24606801 | doi = 10.2174/1381612820666140306095106 }} It was first described by John Holloszy in the 1960s, when it was discovered that physical endurance training induced higher mitochondrial content levels, leading to greater glucose uptake by muscles.{{cite journal | vauthors = Holloszy JO | title = RRegulation of Mitochondrial Biogenesis and GLUT4 Expression by Exercise | journal = Comprehensive Physiology | volume = 1 | issue = 2 | pages = 921–40 | date = April 2011 | pmid = 23737207 | doi = 10.1002/cphy.c100052 | isbn = 9780470650714 }} Mitochondrial biogenesis is activated by numerous different signals during times of cellular stress or in response to environmental stimuli, such as aerobic exercise.{{cite journal | vauthors = Boushel R, Lundby C, Qvortrup K, Sahlin K | title = Mitochondrial plasticity with exercise training and extreme environments | journal = Exercise and Sport Sciences Reviews | volume = 42 | issue = 4 | pages = 169–74 | date = October 2014 | pmid = 25062000 | doi = 10.1249/JES.0000000000000025 | s2cid = 39267910 | doi-access = free }}

Background

The ability for a mitochondrion to self-replicate is rooted in its evolutionary history. It is commonly thought that mitochondria descend from cells that formed endosymbiotic relationships with α-protobacteria; they have their own genome for replication. However, recent evidence suggests that mitochondria may have evolved without symbiosis.{{cite journal |author2-link=Charles Kurland | vauthors = Harish A, Kurland CG | title = Mitochondria are not captive bacteria | journal = Journal of Theoretical Biology | volume = 434 | pages = 88–98 | date = December 2017 | pmid = 28754286 | doi = 10.1016/j.jtbi.2017.07.011 }} The mitochondrion is a key regulator of the metabolic activity of the cell, and is also an important organelle in both production and degradation of free radicals.{{cite journal | vauthors = Bevilacqua L, Ramsey JJ, Hagopian K, Weindruch R, Harper ME | title = Effects of short- and medium-term calorie restriction on muscle mitochondrial proton leak and reactive oxygen species production | journal = American Journal of Physiology. Endocrinology and Metabolism | volume = 286 | issue = 5 | pages = E852-61 | date = May 2004 | pmid = 14736705 | doi = 10.1152/ajpendo.00367.2003 }} It is postulated that higher mitochondrial copy number (or higher mitochondrial mass) is protective for the cell.

Mitochondria are produced from the transcription and translation of genes both in the nuclear genome and in the mitochondrial genome. The majority of mitochondrial protein comes from the nuclear genome, while the mitochondrial genome encodes parts of the electron transport chain along with mitochondrial rRNA and tRNA. Mitochondrial biogenesis increases metabolic enzymes for glycolysis, oxidative phosphorylation and ultimately a greater mitochondrial metabolic capacity. However, depending on the energy substrates available and the redox state of the cell, the cell may increase or decrease the number and size of mitochondria.{{cite journal | vauthors = Mishra P, Chan DC | title = Metabolic regulation of mitochondrial dynamics | journal = The Journal of Cell Biology | volume = 212 | issue = 4 | pages = 379–87 | date = February 2016 | pmid = 26858267 | pmc = 4754720 | doi = 10.1083/jcb.201511036 }} Critically, mitochondrial numbers and morphology vary according to cell type and context-specific demand, whereby the balance between mitochondrial fusion/fission regulates mitochondrial distribution, morphology, and function.{{cite journal | vauthors = Bertholet AM, Delerue T, Millet AM, Moulis MF, David C, Daloyau M, Arnauné-Pelloquin L, Davezac N, Mils V, Miquel MC, Rojo M, Belenguer P | display-authors = 6 | title = Mitochondrial fusion/fission dynamics in neurodegeneration and neuronal plasticity | journal = Neurobiology of Disease | volume = 90 | pages = 3–19 | date = June 2016 | pmid = 26494254 | doi = 10.1016/j.nbd.2015.10.011 | s2cid = 12627451 }}

Protein import

File:Mitochondrial protein import.svg

Since the majority of mitochondrial protein comes from the nuclear genome, the proteins need to be properly targeted and transported into the mitochondria to perform their functions.{{cite journal | vauthors = Dudek J, Rehling P, van der Laan M | title = Mitochondrial protein import: common principles and physiological networks | journal = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | volume = 1833 | issue = 2 | pages = 274–85 | date = February 2013 | pmid = 22683763 | doi = 10.1016/j.bbamcr.2012.05.028 | doi-access = free | hdl = 11858/00-001M-0000-000E-CAAB-9 | hdl-access = free }} First, mRNA is translated in the cell's cytosol. The resulting unfolded precursor proteins will then be able to reach their respective mitochondrial compartments. Precursor proteins will be transported to one of four areas of the mitochondria, which include the outer membrane, inner membrane, intermembrane space, and matrix. All proteins will enter the mitochondria by a translocase on the outer mitochondrial membrane (TOM). Some proteins will have an N-terminal targeting signal, and these proteins will be detected and transported into the matrix, where they will then be cleaved and folded.{{cite journal | vauthors = Ventura-Clapier R, Garnier A, Veksler V | title = Transcriptional control of mitochondrial biogenesis: the central role of PGC-1alpha | journal = Cardiovascular Research | volume = 79 | issue = 2 | pages = 208–17 | date = July 2008 | pmid = 18430751 | doi = 10.1093/cvr/cvn098 | doi-access = free }}{{cite journal | vauthors = Baker MJ, Frazier AE, Gulbis JM, Ryan MT | title = Mitochondrial protein-import machinery: correlating structure with function | journal = Trends in Cell Biology | volume = 17 | issue = 9 | pages = 456–64 | date = September 2007 | pmid = 17825565 | doi = 10.1016/j.tcb.2007.07.010 }} Other proteins may have targeting information in their sequences and will not include an N-terminal signal. During the past two decades, researchers have discovered over thirty proteins that participate in mitochondrial protein import. As researchers learn more about these proteins and how they reach the respective mitochondrial compartments that utilize them, it becomes evident that there is a multitude of processes that work together in the cell to allow for mitochondrial biogenesis.

Fusion and fission

Mitochondria are highly versatile and are able to change their shape through fission and fusion events. Definitively, fission is the event of a single entity breaking apart, whereas fusion is the event of two or more entities joining to form a whole. The processes of fission and fusion oppose each other and allow the mitochondrial network to constantly remodel itself. If a stimulus induces a change in the balance of fission and fusion in a cell, it could significantly alter the mitochondrial network. For example, an increase in mitochondrial fission would create many fragmented mitochondria, which has been shown to be useful for eliminating damaged mitochondria and for creating smaller mitochondria for efficient transporting to energy-demanding areas.{{cite journal | vauthors = Youle RJ, van der Bliek AM | title = Mitochondrial fission, fusion, and stress | journal = Science | volume = 337 | issue = 6098 | pages = 1062–5 | date = August 2012 | pmid = 22936770 | pmc = 4762028 | doi = 10.1126/science.1219855 }}{{cite journal | vauthors = Bo H, Zhang Y, Ji LL | title = Redefining the role of mitochondria in exercise: a dynamic remodeling | journal = Annals of the New York Academy of Sciences | volume = 1201 | pages = 121–8 | date = July 2010 | pmid = 20649548 | doi = 10.1111/j.1749-6632.2010.05618.x | s2cid = 33936266 }} Therefore, achieving a balance between these mechanisms allows a cell to have the proper organization of its mitochondrial network during biogenesis and may have an important role in muscle adaptation to physiological stress.

File:Mitochondrial Fission and Fusion .png

In mammals, mitochondrial fusion and fission are both controlled by GTPases of the dynamin family. The process of mitochondrial fission is directed by Drp1, a member of the cytosolic dynamin family. This protein forms a spiral around mitochondria and constricts to break apart both the outer and inner membranes of the organelle. On the other hand, the process of fusion is directed by different membrane-anchored dynamin proteins at different levels of the mitochondria. Fusion at the level of the outer mitochondrial membrane is mediated by Mfn1 and Mfn2 (Mitofusins 1 and 2), and fusion at the level of the inner mitochondrial membrane is mediated by Opa1. Multiple research studies have observed correlated increases between mitochondrial respiratory capacity with Mfn1, Mnf2, and Drp1 gene expression after endurance exercises.{{cite journal | vauthors = Cartoni R, Léger B, Hock MB, Praz M, Crettenand A, Pich S, Ziltener JL, Luthi F, Dériaz O, Zorzano A, Gobelet C, Kralli A, Russell AP | display-authors = 6 | title = Mitofusins 1/2 and ERRalpha expression are increased in human skeletal muscle after physical exercise | journal = The Journal of Physiology | volume = 567 | issue = Pt 1 | pages = 349–58 | date = August 2005 | pmid = 15961417 | pmc = 1474174 | doi = 10.1113/jphysiol.2005.092031 }} Therefore, it is supported that reorganization of the mitochondrial network in muscle cells plays an important role in response to exercise.

Regulation

PGC-1α, a member of the peroxisome proliferator-activated receptor gamma (PGC) family of transcriptional coactivators, is the master regulator of mitochondrial biogenesis.{{cite journal | vauthors = Johri A, Chandra A, Flint Beal M | title = PGC-1α, mitochondrial dysfunction, and Huntington's disease | journal = Free Radical Biology & Medicine | volume = 62 | pages = 37–46 | date = September 2013 | pmid = 23602910 | pmc = 3722269 | doi = 10.1016/j.freeradbiomed.2013.04.016 }} It is known to co-activate nuclear respiratory factor 2 (NRF2/GABPA), and together with NRF-2 coactivates nuclear respiratory factor 1 (NRF1). The NRFs, in turn, activate the mitochondrial transcription factor A (tfam), which is directly responsible for transcribing nuclear-encoded mitochondrial proteins. This includes both structural mitochondrial proteins as well as those involved in mtDNA transcription, translation, and repair. PGC-1β, a protein that is structurally similar to PGC-1α, is also involved in regulating mitochondrial biogenesis, but differs in that it does not get increased in response to exercise.{{cite journal | vauthors = Jornayvaz FR, Shulman GI | title = Regulation of mitochondrial biogenesis | journal = Essays in Biochemistry | volume = 47 | pages = 69–84 | year = 2010 | pmid = 20533901 | pmc = 3883043 | doi = 10.1042/bse0470069 }} While there have been significant increases in mitochondria found in tissues where PGC-1α is overexpressed, as the cofactor interacts with these key transcription factors, knockout mice with disrupted PGC-1α are still viable and show normal mitochondrial abundance.{{cite journal | vauthors = Lin J, Wu PH, Tarr PT, Lindenberg KS, St-Pierre J, Zhang CY, Mootha VK, Jäger S, Vianna CR, Reznick RM, Cui L, Manieri M, Donovan MX, Wu Z, Cooper MP, Fan MC, Rohas LM, Zavacki AM, Cinti S, Shulman GI, Lowell BB, Krainc D, Spiegelman BM | display-authors = 6 | title = Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1alpha null mice | journal = Cell | volume = 119 | issue = 1 | pages = 121–35 | date = October 2004 | pmid = 15454086 | doi = 10.1016/j.cell.2004.09.013 | doi-access = free }} Thus, PGC-1α is not required for normal development of mitochondria in mice, but when put under physiological stress, these mice exhibit diminished tolerance compared to mice with normal levels of PGC-1α. Similarly, in knockout mice with disrupted PGC-1β, the mice showed mostly normal levels of mitochondrial function with decreased ability to adapt to physiological stress.{{cite journal | vauthors = Scarpulla RC | title = Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network | journal = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | volume = 1813 | issue = 7 | pages = 1269–78 | date = July 2011 | pmid = 20933024 | pmc = 3035754 | doi = 10.1016/j.bbamcr.2010.09.019 }} However, a double knockout experiment of PGC-1α/β created mice that died mostly within 24 hours by defects in mitochondrial maturation of cardiac tissue.{{cite journal | vauthors = Lai L, Leone TC, Zechner C, Schaeffer PJ, Kelly SM, Flanagan DP, Medeiros DM, Kovacs A, Kelly DP | display-authors = 6 | title = Transcriptional coactivators PGC-1alpha and PGC-lbeta control overlapping programs required for perinatal maturation of the heart | journal = Genes & Development | volume = 22 | issue = 14 | pages = 1948–61 | date = July 2008 | pmid = 18628400 | pmc = 2492740 | doi = 10.1101/gad.1661708 }} These findings suggest that while both PGC-1α and PGC- 1β do not each solely establish a cell's ability to perform mitochondrial biogenesis, together they are able to complement each other for optimal mitochondrial maturation and function during periods of physiological stress.

AMP-activated kinase (AMPK) also regulates mitochondrial biogenesis by phosphorylating and activating PGC-1α upon sensing an energy deficiency in muscle. In mice with reduced ATP/AMP ratios that would occur during exercise, the energy depletion has been shown to correlate with AMPK activation. AMPK activation then continued to activate PGC- 1α and NRFs in these mice, and mitochondrial biogenesis was stimulated.

Aging

The capacity for mitochondrial biogenesis has been shown to decrease with age, and such decreased mitochondrial function has been associated with diabetes and cardiovascular disease.{{cite journal | vauthors = Handy DE, Loscalzo J | title = Redox regulation of mitochondrial function | journal = Antioxidants & Redox Signaling | volume = 16 | issue = 11 | pages = 1323–67 | date = June 2012 | pmid = 22146081 | pmc = 3324814 | doi = 10.1089/ars.2011.4123 }}{{cite journal | vauthors = David R | title = Ageing: Mitochondria and telomeres come together | journal = Nature Reviews. Molecular Cell Biology | volume = 12 | issue = 4 | pages = 204 | date = April 2011 | pmid = 21407239 | doi = 10.1038/nrm3082 | doi-access = free }}{{cite journal | vauthors = Hagen TM, Wehr CM, Ames BN | title = Mitochondrial decay in aging. Reversal through supplementation of acetyl-L-carnitine and N-tert-butyl-alpha-phenyl-nitrone | journal = Annals of the New York Academy of Sciences | volume = 854 | pages = 214–23 | date = November 1998 | pmid = 9928432 | doi = 10.1111/j.1749-6632.1998.tb09904.x | s2cid = 25332524 }} Aging and disease can induce changes in the expression levels of proteins involved in the fission and fusion mechanisms of mitochondria, thus creating dysfunctional mitochondria.{{cite journal | vauthors = Sahin E, DePinho RA | title = Axis of ageing: telomeres, p53 and mitochondria | journal = Nature Reviews. Molecular Cell Biology | volume = 13 | issue = 6 | pages = 397–404 | date = May 2012 | pmid = 22588366 | pmc = 3718675 | doi = 10.1038/nrm3352 }} One hypothesis for the detrimental results of aging is associated with the loss of telomeres, the end segments of chromosomes that protect genetic information from degradation. Telomere loss has also been associated with decreased mitochondrial function. Deficiency of telomerase reverse transcriptase (TERT), an enzyme that plays a role in preserving telomeres, has been correlated with activated p53, a protein that suppresses PGC-1α.{{cite journal | vauthors = Sahin E, Colla S, Liesa M, Moslehi J, Müller FL, Guo M, Cooper M, Kotton D, Fabian AJ, Walkey C, Maser RS, Tonon G, Foerster F, Xiong R, Wang YA, Shukla SA, Jaskelioff M, Martin ES, Heffernan TP, Protopopov A, Ivanova E, Mahoney JE, Kost-Alimova M, Perry SR, Bronson R, Liao R, Mulligan R, Shirihai OS, Chin L, DePinho RA | display-authors = 6 | title = Telomere dysfunction induces metabolic and mitochondrial compromise | journal = Nature | volume = 470 | issue = 7334 | pages = 359–65 | date = February 2011 | pmid = 21307849 | pmc = 3741661 | doi = 10.1038/nature09787 }} Therefore, the loss of telomeres and TERT that comes with aging has been associated with impaired mitochondrial biogenesis. AMPK expression has also been shown to diminish with age, which may also contribute to suppressing mitochondrial biogenesis.

Clinical applications of targeting mitochondrial biogenesis

Mitochondrial biogenesis can be targeted to prevent cancer proliferation. Specifically, two biogenesis regulators—PGC1α and c-Myc—can be targeted to prevent cancer proliferation. PGC1α is a key component in mitochondrial biogenesis—as a transcriptional coactivator, it targets multiple transcription factors and the estrogen-related receptor alpha (ERRα).{{cite journal |last1=Scarpulla |first1=Richard |title=Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network |journal=Biochim Biophys Acta |date=2011 |volume=1813 |issue=7 |pages=1269–1278 |doi=10.1016/j.bbamcr.2010.09.019|pmid=20933024 |pmc=3035754 |doi-access=free }} Compounds that target the pathway between PGC1α and ERRα, such as the ERRα inverse agonist, XCT-790, have been found to significantly decrease mitochondrial biogenesis, thus greatly reducing cancer cells’ proliferation and increasing their sensitivity to chemotherapeutic agents.{{cite journal |last1=Kokabu |first1=Tetsuya |last2=Mori |first2=Taisuke |last3=Matsushima |first3=Hiroshi |last4=Yoriki |first4=Kaori |last5=Kataoka |first5=Hisashi |last6=Tarumi |first6=Yosuke |last7=Kitawaki |first7=Jo |title=Antitumor effect of XCT790, an ERRα inverse agonist, on ERα-negative endometrial cancer cells |journal=Cell Oncol (Dordr) |date=2019 |volume=42 |issue=2 |pages=223–235 |doi=10.1007/s13402-019-00423-5|pmid=30706380 |s2cid=256111946 }} c-Myc, a transcription factor, can be inhibited during its dimerization with Max protein by molecules such as IIA6B17{{cite journal |last1=Lu |first1=Xiaohong |last2=Vogt |first2=Peter |last3=Boger |first3=Dale |last4=Lunec |first4=John |title=Disruption of the MYC transcriptional function by a small-molecule antagonist of MYC/MAX dimerization |journal=Oncol. Rep. |series=Medical Radiology |date=2008 |volume=19 |issue=3 |pages=825–830 |doi=10.1007/978-3-540-77385-6 |pmid=18288422|isbn=978-3-540-77384-9 }} and omomyc.{{cite journal |last1=Demma |first1=Mark |last2=Mapelli |first2=Claudio |last3=Sun |first3=Angie |last4=Bodea |first4=Smaranda |last5=Ruprecht |first5=Benjamin |last6=Javaid |first6=Sarah |last7=Wiswell |first7=Derek |last8=Muise |first8=Eric |last9=Chen |first9=Shiyang |last10=Zelina |first10=John |last11=Orvieto |first11=Federica |last12=Santoprete |first12=Alessia |last13=Altezza |first13=Simona |last14=Tucci |first14=Federica |last15=Escandon |first15=Enrique |last16=Hall |first16=Brian |last17=Ray |first17=Kallol |last18=Walji |first18=Abbas |last19=O'Neil |first19=Jennifer |title=Omomyc Reveals New Mechanisms To Inhibit the MYC Oncogene |journal=Mol Cell Biol |date=2019 |volume=39 |issue=22 |pages=e00248-19 |doi=10.1128/MCB.00248-19|pmid=31501275 |pmc=6817756}} Inhibition of the c-Myc-Max complex can block the cell cycle and induce apoptosis in cancer cells.