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The Mitochondrial Nucleoid: Integrating Mitochondrial DNA Into Cellular Homeostasis

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The Mitochondrial Nucleoid: Integrating Mitochondrial DNA Into Cellular Homeostasis Downloaded from http://cshperspectives.cshlp.org/ on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press The Mitochondrial Nucleoid: Integrating Mitochondrial DNA into Cellular Homeostasis Robert Gilkerson1,2, Liliana Bravo1, Iraselia Garcia1, Norma Gaytan1, Alan Herrera1, Alicia Maldonado2, and Brandi Quintanilla1 1Department of Biology, University of Texas-Pan American, Edinburg, Texas 78539-2999 2Department of Clinical Laboratory Sciences, University of Texas-Pan American, Edinburg, Texas 78539-2999 Correspondence: [email protected] The packaging of mitochondrial DNA (mtDNA) into DNA-protein assemblies called nucle- oids provides an efficient segregating unit of mtDNA, coordinating mtDNA’s involvement in cellular metabolism. From the early discovery of mtDNA as “extranuclear” genetic material, its organization into nucleoids and integration into both the mitochondrial organellar network and the cell at large via a variety of signal transduction pathways, mtDNA is a crucial component of the cell’s homeostatic network. The mitochondrial nucleoid is com- posed of a set of DNA-binding core proteins involved in mtDNA maintenance and transcrip- tion, and a range of peripheral factors, which are components of signaling pathways controlling mitochondrial biogenesis, metabolism, apoptosis, and retrograde mitochon- dria-to-nucleus signaling. The molecular interactions of nucleoid components with the organellar network and cellular signaling pathways provide exciting clues to the dynamic integration of mtDNA into cellular metabolic homeostasis. ORIGINS: “EXTRANUCLEAR DNA” AND later confirmed by the similarity of mtDNA to BIOENERGETICS bacterial, rather than human nuclear, DNA. This “extranuclear” DNA is in fact essential for istorically, it has been clear that mitochon- mitochondrial ATP production (DiMauro and Hdria play by theirown rules. Beginning with Schon 2003). the observations that mitochondria indepen- The 16,569 bp circular human mtDNA en- dently synthesize protein (McLean et al. 1958) codes two tRNAs, 22 rRNAs, and 13 polypep- and RNA (Wintersberger 1964), followed by tides necessary for the proper assembly and the discovery of DNAwithin the organelle (Nass function of the mitochondrial complexes of ox- et al. 1965; Nass 1969), mitochondria have idative phosphorylation (OXPHOS) (Anderson emerged as a highly distinct organellar system et al. 1981), which are located in the mitochon- for providing ATP to the cell. The then-contro- drial inner membrane. Complexes I, II, III, and versial endosymbiont theory (Sagan 1967), pro- IV transfer electrons, ultimately donating them posing that mitochondria are descended from to molecularoxygen, to create the chemiosmotic proteobacteria engulfed by eukaryotic cells, was proton-motive gradient (Dcm) which is used Editors: Douglas C. Wallace and Richard J. Youle Additional Perspectives on Mitochondria available at www.cshperspectives.org Copyright # 2013 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a011080 Cite this article as Cold Spring Harb Perspect Biol 2013;5:a011080 1 Downloaded from http://cshperspectives.cshlp.org/ on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press R. Gilkerson et al. by complex V,the F1F0 ATPsynthase, to synthe- mutation), but when the mutation load exceeds size ATP from ADP and Pi. These complexes are the threshold of function, the cell can no longer large, multisubunit macromolecularassemblies, maintain mitochondrial function (DiMauro in which all but a small handful of polypeptides and Schon 2003). are encoded by nuclear genes. The assembly of In addition to the classical mitochondrial these complexes requires the coordination of diseases, mtDNA mutations and defects are both nuclear and mitochondrial transcription emerging in a variety of prevalent human dis- and translation, followed by complex assembly eases in disparate tissues, such as Parkinson dis- in the mitochondria and insertion into the inner ease (Bender et al. 2006; Kraytsberg et al. 2006), membrane. The necessity of producing and multiple sclerosis (Campbell et al. 2012), heart assembling complexes of polypeptides derived failure (Karamanlidis et al. 2010), diabetes from both chromosomal and organellar ge- (Ritov et al. 2010), and aging (Bender et al. nomes means that mitochondria are susceptible 2006). The crucial role of mtDNA in cellular to mutations in either. metabolism and bioenergetics, as well as its pro- Defects of both nuclear DNA and mtDNA found importance to human health, motivates a have been shown to have devastating conse- better understanding of the elegant complexity quences for bioenergetics in human health. Mu- of mtDNA’s macromolecular organization and tations in nuclear-encoded factors such as mi- integration into both the organellar network tochondrial DNA polymerase g (POLG) and and cell at large. Despite the bioenergetic impor- thymidine kinase 2 (TK2) cause depletion of tance and medical relevance of mtDNA, a num- mtDNA and increased mtDNA mutation, fre- ber of misconceptions regarding its organiza- quently manifesting as neuromuscular disease tion have persisted. MtDNA has often been (Oskoui et al. 2006; Akman et al. 2008). Muta- thought to exist in a “naked” or unprotected tions or depletion of mtDNA cause a range of state. However, mtDNA is efficiently packaged neuromuscular disorders, such as the classical into a macromolecular assembly that allows for mitochondrial diseases Kearns-Sayre syndrome dynamic genetic maintenance and integration (KSS), which is caused by large-scale deletions into cellular signaling. of mtDNA (D-mtDNAs), and myoclonus epi- lepsy with lactic acidosis and stroke-like epi- sodes (MELAS), which is caused by point mu- THE NUCLEOID: A MACROMOLECULAR ASSEMBLY FOR MITOCHONDRIAL tations in mtDNA-encoded tRNAs (reviewed in GENETICS DiMauro and Schon 2003; Greaves et al. 2012). Although each of the mitochondrial neuromus- Given their endosymbiotic bacterial origins, it is cular disorders is individually rare, pathogenic not surprising that the organization of mtDNA mtDNA mutations as a whole occur at a high is similar to that of bacterial DNA. The bacterial frequency of 1:200 individuals (Elliott et al. genome undergoes a 104-fold compaction of 2008; Greaves et al. 2012). The study of mito- its volume to form the bacterial nucleoid chondrial neuromuscular disorders has uncov- (de Vries 2010). Similarly, the mitochondrial ered fundamental concepts of genotype-pheno- nucleoid typically has a diameter of 100 nm type relationships for mtDNA mutations and (Kukat et al. 2011), whereas a completely relaxed mitochondrial function. Typically, wild-type 16.6 kb circular DNAwould have a length on the and mutant mtDNAs exist side by side within order of 2 mm within the mitochondrial ma- thesame cellandtissue,asituation calledhetero- trix. Beginning with the original fluorescence plasmy. The relative proportions of the two micrographs of human mtDNA within the cell mtDNAvariants is a crucial determinant of mi- (Satoh and Kuroiwa 1991), nucleoids have been tochondrial function in cells carrying mutant clearly evident by microscopy as discrete punc- mtDNAs: Cells can typically withstand a very tae distributed throughout the mitochondrial high overall mtDNA mutation load (often network (Alam et al. 2003; Legros et al. 2004). 80%–90%, depending on the nature of the This punctate appearance reveals the unique 2 Cite this article as Cold Spring Harb Perspect Biol 2013;5:a011080 Downloaded from http://cshperspectives.cshlp.org/ on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press Dynamics of the Mitochondrial Nucleoid organization of mtDNA within the organellar mitochondrial single-strand binding protein network. The mitochondrial nucleoid is com- (mtSSB), POLG, and mtRNA polymerase posed of a range of proteins with a diverse array (POLRMT), which were found in both cross- of functions, from DNA packaging and tran- linked and native nucleoid fractions of HeLa scription to factors with broader signaling func- cells (Bogenhagen et al. 2008). TFAM is a 24- tions, facilitating mtDNA’s integration into kDa protein with two high-mobility group crucial cell-wide metabolic and proliferative sig- (HMG)-box domains. HMG-family proteins naling networks. Nucleoid packaging provides are able to bend, wrap, and unwind DNA. Al- an efficient means of ensuring that mitochon- though it was early identified as a transcription drial genetic material is distributed throughout factor for mtDNA (Fisher and Clayton 1985), the cell’s mitochondria and is responsive to cel- it has become clear that TFAM plays an equal- lular metabolic needs. ly important role as a packaging protein for The packaging of mtDNA into nucleoids is mtDNA (Alam et al. 2003). TFAM packages mediated by the nucleoid’s protein components. DNA in vitro (Kaufman et al. 2007) and colo- As the different individual protein factors of the calizes with mtDNA in nucleoids by immuno- nucleoid have been cataloged, the macromolec- microscopy (Iborra et al. 2004; Legros et al. ular structure of the nucleoid has been suggest- 2004). Crystallographic studies have shown that ed to consist of a core domain comprised of key TFAM induces U-turn bends in DNA (Ngo et mtDNA-associated proteins, and a peripheral al. 2011; Rubio-Cosials et al. 2011). Nucleoids zone, consisting of factors which are less consti- tightly package mtDNA, to the extent that freely tutively bound, many of which have important diffusible matrix protein is excluded from the
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