The Mitochondrial Nucleoid: Integrating Mitochondrial DNA into Cellular Homeostasis

Gilkerson, Robert; Bravo, Liliana; Garcia, Iraselia; Gaytan, Norma; Herrera, Alan; Maldonado, Alicia Martín Lagos; Quintanilla, Brandi

doi:10.1101/cshperspect.a011080

Cited by 119 publications

(87 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…38,39 The core mtDNA nucleoid components center consists of transcription and replication factors, such as TFAM (the transcription factor A, mitochondrial), POLG (the mtDNA polymerase γ), Twinkle (the mtDNA helicase), mtSSB (the mitochondrial single-strand DNA-binding protein) 38,39 and LONP1 (the Lon protease), were found to be an integral mtDNA nucleoid factor; and ATAD3, PHB1 and PHB2 (Prohibitin1 and Prohibitin2) provide molecular scaffolding to stabilize mtDNA nucleiod and promote mitochondrial translation; 38,39 in addition, AFG3L2, a subunit of mitochondrial m-AAA protease, is associated with mtDNA nucleiod. 38 Upon Mic60/Mitofilin depletion, the protein levels of TFAM and POLG were not altered ( Figure 6b); however, LONP1 and AFG3L2 were decreased in shMic60 MEFs ( Figure 6b); importantly, mtSSB, Twinkle, ATAD3, PHB1 and PHB2 were remarkably decreased upon Mic60/Mitofilin depletion (Figure 6b).…”

Section: Mic60 Knockdown Attenuates the Transcription Of Mtdnamentioning

confidence: 99%

“…mtDNA is associated with several proteins and packaged into nucleoprotein complexes called 'mitochondrial nucleoids' or 'mtDNA nucleoids'. 38,39 mtDNA nucleoids are crucial for the biogenesis and maintenance of mtDNA. 40 mtDNA nucleoids are dynamic and relatively uniform in shape and size, 41 but the factors for controlling the distribution and organization of mtDNA nucleoids remain to be explored.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Mic60/Mitofilin determines MICOS assembly essential for mitochondrial dynamics and mtDNA nucleoid organization

et al. 2015

View full text Add to dashboard Cite

The MICOS complex (mitochondrial contact site and cristae organizing system) is essential for mitochondrial inner membrane organization and mitochondrial membrane contacts, however, the molecular regulation of MICOS assembly and the physiological functions of MICOS in mammals remain obscure. Here, we report that Mic60/Mitofilin has a critical role in the MICOS assembly, which determines the mitochondrial morphology and mitochondrial DNA (mtDNA) organization. The downregulation of Mic60/Mitofilin or Mic19/CHCHD3 results in instability of other MICOS components, disassembly of MICOS complex and disorganized mitochondrial cristae. We show that there exists direct interaction between Mic60/Mitofilin and Mic19/CHCHD3, which is crucial for their stabilization in mammals. Importantly, we identified that the mitochondrial i-AAA protease Yme1L regulates Mic60/Mitofilin homeostasis. Impaired MICOS assembly causes the formation of 'giant mitochondria' because of dysregulated mitochondrial fusion and fission. Also, mtDNA nucleoids are disorganized and clustered in these giant mitochondria in which mtDNA transcription is attenuated because of remarkable downregulation of some key mtDNA nucleoid-associated proteins.Together, these findings demonstrate that Mic60/Mitofilin homeostasis regulated by Yme1L is central to the MICOS assembly, which is required for maintenance of mitochondrial morphology and organization of mtDNA nucleoids. Mitochondria have a key role in oxidative phosphorylation and related cellular metabolism, in energy conversion, in programmed cell death, in cell growth and in diseases. Mitochondrial outer and inner membranes strongly differ in architecture and functions. The mitochondrial outer membrane forms a barrier to cytosol, and contains channels and the translocases of outer membrane, which is the main protein entry gate of mitochondria. 1,2 In contrast, the mitochondrial inner membrane consists of two morphologically distinct regions: the inner boundary membrane is in close proximity to the outer membrane and the cristae membranes that are large tubular invaginations. [3][4][5][6][7][8] The mitochondrial inner boundary and cristae membrane are physically separated by cristae junctions, which are narrow tubular or slot-like structure. 4,9 The mitochondrial cristae are arranged in regular arrays and are the main sites of ATP production in the mitochondria, but the molecules that are associated with the maintenance of cristae architecture still remain elusive. Recently, several groups identified a large protein complex, MICOS complex (mitochondrial contact site and cristae organizing system; previously named MINOS, MitOS, Mitofilin or Fcj1 complex ), that has a crucial role in the formation of cristae junctions, contact sites to the outer membrane, and the organization of inner membrane. [10][11][12][13][14] In yeast, MICOS consists of at least six subunits: Mic60 (Fcj1), Mic10 (Mio10/Mcs10/Mos1), Mic19 (Aim13/Mcs19), Mic26 (Mio27/Mcs29/Mos2), Mic12 (Aim5/ Msc12) and Mic27 (Aim37/Mcs27). In mammals, five s...

show abstract

Section: Mic60 Knockdown Attenuates the Transcription Of Mtdnamentioning

confidence: 99%

mentioning

confidence: 99%

Mic60/Mitofilin determines MICOS assembly essential for mitochondrial dynamics and mtDNA nucleoid organization

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Although no nucleosome-like structures have been identified in mitochondria, mtDNA is bound by a variety of structural and regulatory proteins, creating a structure similar to the bacterial nucleoid (Gilkerson et al, 2013). To identify potential protein partners of SWIB5, we analyzed if SWIB5 could heterodimerize with other SWIB proteins localized in mitochondria.…”

Section: Swib5 Interacts With Other Mitochondrial Swib Proteinsmentioning

confidence: 99%

The Mitochondrial DNA (mtDNA)-Associated Protein SWIB5 Influences mtDNA Architecture and Homologous Recombination

et al. 2017

View full text Add to dashboard Cite

In addition to the nucleus, mitochondria and chloroplasts in plant cells also contain genomes. Efficient DNA repair pathways are crucial in these organelles to fix damage resulting from endogenous and exogenous factors. Plant organellar genomes are complex compared with their animal counterparts, and although several plant-specific mediators of organelle DNA repair have been reported, many regulators remain to be identified. Here, we show that a mitochondrial SWI/SNF (nucleosome remodeling) complex B protein, SWIB5, is capable of associating with mitochondrial DNA (mtDNA) in Arabidopsis thaliana. Gain-and loss-of-function mutants provided evidence for a role of SWIB5 in influencing mtDNA architecture and homologous recombination at specific intermediate-sized repeats both under normal and genotoxic conditions. SWIB5 interacts with other mitochondrial SWIB proteins. Gene expression and mutant phenotypic analysis of SWIB5 and SWIB family members suggests a link between organellar genome maintenance and cell proliferation. Taken together, our work presents a protein family that influences mtDNA architecture and homologous recombination in plants and suggests a link between organelle functioning and plant development.

show abstract

“…In addition, mitochondrial DNA is only loosely coated to form a nucleoid structure (50), unlike the chromatin structure in the genome. In 2008, two independent research groups reported rather detailed mtBER mechanisms and although there was a major difference at one BER reaction step, they were at most points in agreement and have been regarded as the framework model of mtBER.…”

Section: Subcellular Localization Of Ape1mentioning

confidence: 99%

Repair of Oxidative DNA Damage and Cancer: Recent Progress in DNA Base Excision Repair

Scott

Rangaswamy

Wicker

et al. 2014

Antioxidants & Redox Signaling

137

View full text Add to dashboard Cite

Significance: Reactive oxygen species (ROS) are generated by exogenous and environmental genotoxins, but also arise from mitochondria as byproducts of respiration in the body. ROS generate DNA damage of which pathological consequence, including cancer is well established. Research efforts are intense to understand the mechanism of DNA base excision repair, the primary mechanism to protect cells from genotoxicity caused by ROS. Recent Advances: In addition to the notion that oxidative DNA damage causes transformation of cells, recent studies have revealed how the mitochondrial deficiencies and ROS generation alter cell growth during the cancer transformation. Critical Issues: The emphasis of this review is to highlight the importance of the cellular response to oxidative DNA damage during carcinogenesis. Oxidative DNA damage, including 7,8-dihydro-8-oxoguanine, play an important role during the cellular transformation. It is also becoming apparent that the unusual activity and subcellular distribution of apurinic/apyrimidinic endonuclease 1, an essential DNA repair factor/redox sensor, affect cancer malignancy by increasing cellular resistance to oxidative stress and by positively influencing cell proliferation. Future Directions: Technological advancement in cancer cell biology and genetics has enabled us to monitor the detailed DNA repair activities in the microenvironment. Precise understanding of the intracellular activities of DNA repair proteins for oxidative DNA damage should provide help in understanding how mitochondria, ROS, DNA damage, and repair influence cancer transformation. Antioxid. Redox Signal. 20,[708][709][710][711][712][713][714][715][716][717][718][719][720][721][722][723][724][725][726]

show abstract

The Mitochondrial Nucleoid: Integrating Mitochondrial DNA into Cellular Homeostasis

Cited by 119 publications

References 70 publications

Mic60/Mitofilin determines MICOS assembly essential for mitochondrial dynamics and mtDNA nucleoid organization

Mic60/Mitofilin determines MICOS assembly essential for mitochondrial dynamics and mtDNA nucleoid organization

The Mitochondrial DNA (mtDNA)-Associated Protein SWIB5 Influences mtDNA Architecture and Homologous Recombination

Repair of Oxidative DNA Damage and Cancer: Recent Progress in DNA Base Excision Repair

Contact Info

Product

Resources

About