Transcriptional changes in OXPHOS complex I deficiency are related to anti-oxidant pathways and could explain the disturbed calcium homeostasis

Abstract

Defective complex I (CI) is the most common type of oxidative phosphorylation disease, with an incidence of 1 in 5000 live births. Here, whole genome expression profiling of fibroblasts from CI deficient patients was performed to gain insight into the cell pathological mechanism. Our results suggest that patient fibroblasts responded to oxidative stress by Nrf2-mediated induction of the glutathione antioxidant system and Gadd45-mediated activation of the DNA damage response pathway. Furthermore, the observed reduced expression of selenoproteins, might explain the disturbed calcium homeostasis previously described for the patient fibroblasts and might be linked to endoplasmic reticulum stress. These results suggest that both glutathione and selenium metabolism are potentially therapeutic targets in CI deficiency.

How do changes in the mtDNA and mitochondrial dysfunction influence cancer and cancer therapy? Challenges, opportunities and models

“…Electrons from NADH can enter the electron transport chain (ETC), formed by complex I, complex II, complex III and complex IV (I-IV). CI is also known as NADH dehydrogenase/NADH ubiquinone oxidoreductase, the largest of the oxidative phosphorylation (OXPHOS) complexes, and is one of the starting points of enrolling the electrons into the ETC [5]. The ETC transports electrons through the IMM, toward coenzyme Q (Q), after which they are transferred to complex III (III).…”

“…Increased exposure to this OXPHOS-related superoxide may not only affect the nearby located mtDNA but also the nuclear DNA (nDNA), proteins and lipids, resulting in impaired proteins and/or enhanced reactive oxygen species (ROS) production [4]. mtDNA mutations can lead to a decreased efficiency of the ETC and can cause more ROS production [5,6]. It has been shown both in vitro and in vivo that the OXPHOS system and OXPHOS-related superoxide can have a major influence on tumor progression [7].…”

Oxidative stress, mitochondrial dysfunction and neurodegenerative diseases; a mechanistic insight

“…The hydroxyl radical being highly reactive can damage different macromolecules inside mitochondria like proteins, DNA and lipids [44], and that unrepaired damage to mitochondrial DNA leads to defective complex I or III which can result in increased electron reduction of O 2 to form superoxide [45][46][47]. Increased concentration of superoxide radicals that occurs due to mitochondrial DNA lesions would contribute to metabolic oxidative stress, cellular injury and genomic instability [43].…”

Cellular and animal models for mitochondrial complex I deficiency: A focus on the NDUFS4 subunit

“…Therefore, the increased ROS levels in these fibroblasts might fulfill a signaling role (2,30,31). Indeed, transcriptional analysis suggests that the absence of ROSmediated damage might be due to upregulation of antioxidant defense systems and involves Keap1-Nrf2, glutathione, thioredoxin, and peroxiredoxin (32).…”