Mitochondrial HMG-Box Containing Proteins: From Biochemical Properties to the Roles in Human Diseases

Abstract

Mitochondrial DNA (mtDNA) molecules are packaged into compact nucleo-protein structures called mitochondrial nucleoids (mt-nucleoids). Their compaction is mediated in part by high-mobility group (HMG)-box containing proteins (mtHMG proteins), whose additional roles include the protection of mtDNA against damage, the regulation of gene expression and the segregation of mtDNA into daughter organelles. The molecular mechanisms underlying these functions have been identified through extensive biochemical, genetic, and structural studies, particularly on yeast (Abf2) and mammalian mitochondrial transcription factor A (TFAM) mtHMG proteins. The aim of this paper is to provide a comprehensive overview of the biochemical properties of mtHMG proteins, the structural basis of their interaction with DNA, their roles in various mtDNA transactions, and the evolutionary trajectories leading to their rapid diversification. We also describe how defects in the maintenance of mtDNA in cells with dysfunctional mtHMG proteins lead to different pathologies at the cellular and organismal level.

The yeast mitochondrial succinylome: Implications for regulation of mitochondrial nucleoids

“…Since the majority of the components of the mt-nucleoid were succinylated, it is likely that this PTM plays a role in their metabolism. To investigate the possible functional importance of succinylation in the regulation of the mt-nucleoid, we analyzed the effect of succinylation on the DNA-binding activity of Abf2p, known to mediate the bending and compacting of mtDNA in S. cerevisiae [reviewed in (54)]. Of the twenty-five lysine residues present in the mature form of Abf2p (lacking the mitochondrial targeting sequence) (Figure 4A), thirteen were J o u r n a l P r e -p r o o f succinylated in vivo.…”

“…The possibility that PTMs can play a role in regulation of bacterial and mt-nucleoids has already been discussed elsewhere (54,55). To test the hypothesis that succinylation may play a role in regulation of mt-nucleoid in S. cerevisiae we first checked whether a subset of the succinylated mitochondrial proteins is GO-enriched for a biological process, cellular component, or molecular function linked to mtDNA metabolism.…”

“…Most of the proteins known to associate with the mt-nucleoid are bifunctional (53,57), so assessing the effect of their succinylation on mt-nucleoid-related functions is rather difficult. One protein that is mainly dedicated to compacting the mtDNA into the mt-nucleoid in S. cerevisiae is Abf2p, a mitochondrial HMG-box containing protein (mtHMG protein) that binds and bends mtDNA into higher-order structures (54). The previous proteomic study (19) identified a single J o u r n a l P r e -p r o o f succinylated lysine (K162) in Abf2p.…”

Mitochondrial Kinases and the Role of Mitochondrial Protein Phosphorylation in Health and Disease

“…Mitochondrial DNA is compacted into nucleoids, nucleoprotein complexes that are associated with the IMM [ 270 ]. The most abundant group of nucleoid proteins are the mtDNA-packaging proteins which contain one or two high-mobility group (HMG)-box domains that are critically involved in mtDNA binding and compacting (for review see [ 271 ]). The most studied and best characterized mitochondrial HMG-box proteins are the S. cerevisiae Abf2 (ARS-binding factor 2) and the human mitochondrial transcription factor A (TFAM), both of which are known to be phosphorylated [ 272 , 273 , 274 ].…”

Interactions of Mitochondrial Transcription Factor A with DNA Damage: Mechanistic Insights and Functional Implications

“…This review summarizes recent advances in the biochemical basis of human TFAM-DNA interactions with a focus on the interaction of TFAM with different forms of non-canonical DNA structures. For general discussions on the structure, function, and physiological importance of TFAM, please see excellent reviews [20][21][22][23][24].…”