The Level of ALR is Regulated by the Quantity of Mitochondrial DNA

Abstract

Augmenter of liver regeneration (ALR) contributes to mitochondrial biogenesis, maintenance and to the physiological operation of mitochondria. The depletion of ALR has been widely studied and had serious consequences on the mitochondrial functions. However the inverse direction, the effect of the depletion of mitochondrial electron transfer chain and mtDNA on ALR expression has not been investigated yet. Thus mtDNA depleted, ρ(0) cell line was prepared to investigate the role of mitochondrial electron transfer chain and mtDNA on ALR expression. The depletion of mtDNA has not caused any difference at mRNA level, but at protein level the expression of ALR has been markedly increased. The regulatory role of ATP and ROS levels could be ruled out because the treatment of the parental cell line with different respiratory inhibitors and uncoupling agent could not provoke any changes in the protein level of ALR. The effect of mtDNA depletion on the protein level of ALR has been proved not to be liver specific, since the phenomenon could be observed in the case of two other, non-hepatic cell lines. It seems the level of mtDNA and/or its products may have regulatory role on the protein level of ALR. The up-regulation of ALR can be a part of the adaptive response in ρ(0) cells that preserves the structural integrity and the transmembrane potential despite the absence of protein components encoded by the mtDNA.

In silico Analysis on the Possible Role of Mitochondria in Ferroptosis

“…Mitochondria play a central role in cellular bioenergetics, ROS homeostasis, and in various cell death pathways as in apoptosis and necroptosis [34,35]. Therefore, it is not surprising that the role of mitochondria is continuously investigated in a cell death pathway which has features such as oxidative damage to lipid structures, the involvement of glutathione dependent antioxidant enzymes and the biosynthesis of specific lipid moieties.…”

Vízoldaható antioxidánsok döntéshelyzetben

“…Vizsgálatainkat mitokondriális DNS fosztott sejteken folytatva megállapítottuk, hogy a mitokondriális DNS hiány hatására, a mitokondriális oxidatív folding apparátus fontos eleme, az ALR (Augmenter of Liver Regeneration) fehérjeszintje jelentõs mértékben megnõ. Az ALR mennyisége nem mutatott változást a sejtek légzési komplex gátló és szétkapcsoló szerekkel történõ kezelésére, ezért az ATP, illetve ROS szintek ALR fehérjeszintet szabályozó szerepe nem valószínû 29 . Az ALR részt vesz a mitokondriumok biogenezisében és fenntartásában, ezért könnyen elképzelhetõ, hogy szintjének megemelkedése a mitokondriális DNS fosztott, ñ 0 sejtek adaptív válaszának egy része lehet, amely segít a mtDNS-ben kódolt fehérjék kiesése ellenére a mitokondriális belsõ membrán integritásának és a membránpotenciál megõrzésében.…”

Augmenter of liver regeneration: A fundamental life protein

“…Additional features point to ALR as the central protein of the disulfide relay system: evolutionary divergence in Trypanosoma brucei shows that ALR alone is able to mediate IMS protein folding in the absence of Mia40, and ALR, but not MIA40, responds to alterations of mitochondrial DNA levels or mitochondrial DNA mutation . This second point suggests that ALR could represent a regulatory molecule in this pathway.…”