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Mitochondrial Nucleoid: Shield and Switch of the Mitochondrial Genome 时间:2017-06-13 12:01   来源:未知   作者:admin   点击: 次 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.
1. Introduction
   Normal cellular physiology is critically dependent upon energy in eukaryotic cells, making mitochondria indispensable organelles for energy production in the form of adenosine triphosphate (ATP) via the electron-transport chain and oxidative phosphorylation system (OXPHOS). Additionally, numerous biological functions, including ATP transport, heat production, metal homeostasis, and stress signaling and defense responses, involve mitochondria [1–5]. Stationary (or immobilized) mitochondria serve as calcium buffers to avoid harmful intracellular calcium overload. Depending on cellular demand, their composition is highly variable from tissue to tissue to enable fulfillment of specialized functions, with accumulation at regions of high-energy demand [4, 6]. The position of mitochondria within the cell is determined largely by the cytoskeleton, which comprises a highly dynamic network of actin filaments, microtubules, and intermediate filaments [7, 8]. Mitochondrial movement, which appears to be influenced by intermediate filament proteins, is highly coordinated with changes in organelle shape in order to produce mitochondria with sizes compatible with their movement [9]. Therefore, the correct distribution of mitochondria is achieved by directed movement and docking and anchoring mechanisms [8]. Unlike other subcellular organelles, such as Golgi, lysosomes, and endosomes, mitochondria individually encapsulate their own genome, referred to as mitochondrial DNA (mtDNA). The size range of mtDNAs found in multicellular animals is relatively narrow (~16.5 kb; Figure 1), with some exceptions varying from 14 kb in the nematode to 42 kb in the scallop [10]. However, the mitochondrial genome of higher plants is much larger than that in multicellular animals, ranging from 200 kb to 2400 kb [6, 10]. Many aspects of mtDNA differ from those of nuclear DNA, including its non-Mendelian genetics and the polyploid nature of the genome within a single cell [11,12].
   Mitochondria preserve very complex and unique machinery to maintain and express the content of mtDNA. For example, mtDNA replication occurs independent of the cell cycle and irrespective of the replication of genes in the nucleus [13]. Mutations originating from chromosomal DNA cannot completely explain mitochondrial diseases manifested in cardiomyopathies [14, 15], neurodegenerative diseases, aging [16–18], and cancer. Mitochondrial genomes are not naked but rather packaged into chromosome-like organellar nuclei, termed nucleoids, that exhibit a discrete macromolecular assembly that dictates mtDNA-protein interactions related to mitochondrial genetics [19]. In eukaryotic cells, thousands of mtDNA molecules are organized into several hundred nucleoids [1, 13, 19–24], which function as units of mtDNA propagation for mtDNA replication, segregation, and gene expression [25–28]. As an organizing body of mtDNA, nucleoids work as a platform for the subtle and controlled regulation of mitochondrial genomes and their efficient integration into cellular signaling [26, 29]. Naked mtDNA in the mitochondrial matrix would preclude efficient mtDNA maintenance, resulting in increased accumulation of mutations and the inevitable faulty segregation of mtDNA. Numerous cellular metabolic processes are connected to dynamic regulation associated with mitochondrial nucleoids in order to control the stabilization, maintenance, distribution, and inheritance of the mitochondrial genome [30, 31]. In this review, we addressed the putative mitochondrial nucleoid structure, proteins involved in nucleoid formation, and their regulatory roles in mitochondrial metabolism. Although in-depth mechanistic findings regarding mtDNA nucleoids have been extensively revealed in model organisms, such as Saccharomyces cerevisiae [32], this review will be limited to findings from human and mammalian systems.