Hypoxia Promotes Mitochondrial Complex I Abundance via HIF-1α in Complex III and Complex IV Deficient Cells

Abstract

Murine fibroblasts deficient in mitochondria respiratory complexes III (CIII) and IV (CIV) produced by either the ablation of Uqcrfs1 (encoding for Rieske iron sulfur protein, RISP) or Cox10 (encoding for protoheme IX farnesyltransferase, COX10) genes, respectively, showed a pleiotropic effect in complex I (CI). Exposure to 1–5% oxygen increased the levels of CI in both RISP and COX10 KO fibroblasts. De novo assembly of the respiratory complexes occurred at a faster rate and to higher levels in 1% oxygen compared to normoxia in both RISP and COX10 KO fibroblasts. Hypoxia did not affect the levels of assembly of CIII in the COX10 KO fibroblasts nor abrogated the genetic defect impairing CIV assembly. Mitochondrial signaling involving reactive oxygen species (ROS) has been implicated as necessary for HIF-1α stabilization in hypoxia. We did not observe increased ROS production in hypoxia. Exposure to low oxygen levels stabilized HIF-1α and increased CI levels in RISP and COX10 KO fibroblasts. Knockdown of HIF-1α during hypoxic conditions abrogated the beneficial effect of hypoxia on the stability/assembly of CI. These findings demonstrate that oxygen and HIF-1α regulate the assembly of respiratory complexes.

Propofol via Antioxidant Property Attenuated Hypoxia-Mediated Mitochondrial Dynamic Imbalance and Malfunction in Primary Rat Hippocampal Neurons

“…Although Fis1 was also reported to play a role in mitochondrial fission [ 33 ], we found it was not affected by hypoxia ( Figure 5(a) ). In addition, we reported in hippocampal neurons hypoxia-induced Drp1 expression was due to hypoxia-sensitive transcription factor HIF-1 α ( Figure 6(a) ), which was consistent with previous publications carried out in fibroblasts [ 30 ], cardiac cells [ 22 ], and vascular smooth muscle cells [ 34 ]. Although other transcription factors such as Smad2/3 [ 35 ], NF- κ B [ 36 ], and calcium-related transcription factors [ 37 ] have been reported to correlate with Drp1 expression, we demonstrated that HIF-1 α inhibitors could almost completely inhibit hypoxia-induced Drp1 expression ( Figure 6(b) ), and thus, suggesting the pivotal role of HIF-1 α .…”

“…also reported to play a role in mitochondrial fission [33], we found it was not affected by hypoxia (Figure 5(a)). In addition, we reported in hippocampal neurons hypoxiainduced Drp1 expression was due to hypoxia-sensitive transcription factor HIF-1α (Figure 6(a)), which was consistent with previous publications carried out in fibroblasts [30], cardiac cells [22], and vascular smooth muscle cells [34].…”

“…Furthermore, our data suggested intracellular ROS played a critical role, since both antioxidant and ROS scavenger reduced ROS (Figure 3) and abolished hypoxia-induced mitochondrial malfunction (Figure 3). The pivotal role of ROS during hypoxia-induced mitochondrial malfunction was also supported by previous publications, which demonstrated that hypoxia may impair mitochondrial function through inducing oxidative stress in rat cardiomyocytes [28], human renal tubular cells [29], murine fibroblasts [30], rat cerebral neuronal glial cells [31], and primary rat hippocampal neurons [32]. ), while reduced the phosphorylated of Drp1 at ser 637 (p-Drp1 ser637 ), which were both attenuated by propofol, α-tocopherol, and ebselen.…”

Comprehensive analysis of lower mitochondrial complex I expression is associated with cell metastasis of clear cell renal cell carcinoma

“…It has recently been reported that low oxygen levels stabilized HIF-1α and increased CI levels. Meanwhile, knockdown of HIF-1α abrogated the effect of hypoxia on CI levels ( 31 ). Here, we showed that PPARG can function as a transcription activator for CI genes.…”

“…It has been demonstrated that HIF and hypoxiarelated pathways play critical roles in the development and progress of RCC (26,(29)(30)(31). Small molecule inhibitors that target HIF are promising therapeutical agents for RCC.…”