Mitochondrial Nucleoid: Shield and Switch of the Mitochondrial Genome

Abstract

Mitochondria preserve very complex and distinctively unique machinery to maintain and express the content of mitochondrial DNA (mtDNA). Similar to chromosomes, mtDNA is packaged into discrete mtDNA-protein complexes referred to as a nucleoid. In addition to its role as a mtDNA shield, over 50 nucleoid-associated proteins play roles in mtDNA maintenance and gene expression through either temporary or permanent association with mtDNA or other nucleoid-associated proteins. The number of mtDNA(s) contained within a single nucleoid is a fundamental question but remains a somewhat controversial issue. Disturbance in nucleoid components and mutations in mtDNA were identified as significant in various diseases, including carcinogenesis. Significant interest in the nucleoid structure and its regulation has been stimulated in relation to mitochondrial diseases, which encompass diseases in multicellular organisms and are associated with accumulation of numerous mutations in mtDNA. In this review, mitochondrial nucleoid structure, nucleoid-associated proteins, and their regulatory roles in mitochondrial metabolism are briefly addressed to provide an overview of the emerging research field involving mitochondrial biology.

Figure 1

Human mtDNA. Human mtDNA is circular, with 16,569 bps that encode seven of the 43 subunits of complex I, one of the 11 subunits of complex III (CYTB), three of the 13 subunits of complex IV (COXI, COXII, and COXIII), and two of the 16 subunits of complex V (ATP synthase 6 and ATP synthase 8). It also encodes two ribosomal RNAs and 22 transfer RNAs. ATP, adenosine triphosphate; COX, cyclooxygenase; CYTB, cytochrome B; mtDNA, mitochondrial DNA.

Figure 2

Spatial organization (localization) of mitochondrion and mitochondrial nucleoids. The contour length of circular mtDNA (~16.5 kb) is ~5 μm [47] and requires tight packaging into nucleoids to fit into the tubules of the mitochondrial network comprised of cylinders ~250 nm to ~400 nm in diameter. Nucleoids are organized in higher-ordered assemblies, including respiratory chain supercomplexes [31] and ER-mitochondria complexes (red circle). ER, endoplasmic reticulum; mtDNA, mitochondrial DNA.

Figure 3

mtDNA packaging by TFAM and its degradation by the mitochondrial AAA protease LONP1. Human circular mtDNA is packaged by TFAMs, but their excessive packing of mtDNA may result in shutdown of mtDNA transcription and replication. TFAM can be degraded by the mitochondrial protease LONP1. LonP1, mitochondrial AAA protease; mtDNA, mitochondrial DNA; TFAM, mitochondrial transcription factor A.

Figure 4

Putative nucleoid-associated proteins located in the D-loop region of mtDNA. TFAM, POLG, ATAD3, LONP1, and mtSSB are nucleoid-associated proteins that possibly interact with the D-loop region of mtDNA. These five proteins might exhibit DNA-binding capacity and, therefore, directly associate with mtDNA. ATAD3, ATPase family AAA-domain-containing protein 3; LONP1, mitochondrial AAA protease; mtDNA, mitochondrial DNA; mtSSB mitochondrial single-stranded DNA-binding protein; POLG, mitochondrial polymerase γ; TAFM, mitochondrial transcription factor A.

Figure 5

Spatial organization of nucleoid-associated proteins. Some proteins that exhibit mtDNA-binding capacity are located in the core region, whereas others might interact with proteins in the core region or other mitochondrial proteins. ANT, adenine nucleotide translocator; ATAD3, ATPase family AAA-domain-containing protein 3; HSP60, heat-shock protein 60; LONP1, mitochondrial AAA protease; mAAA, mitochondrial ATPase-associated with various cellular activities (AAA+) protease; mtDNA; mitochondrial DNA; mtSSB, mitochondrial single-stranded DNA-binding protein; mTERF, mitochondrial transcription termination factor; PHB; prohibitin; POLG, mitochondrial polymerase γ; POLRMT, mitochondrial RNA polymerase; TFB1M, mitochondrial transcription factor B1; TFB2M, mitochondrial transcription factor B2.