Mitochondrial Biogenesis Levels Research Articles

5-HT1F receptor regulates mitochondrial homeostasis and its loss potentiates acute kidney injury and impairs renal recovery.

Our laboratory previously reported that agonists of the 5-hydoxytryptamine 1F (5-HT1F) receptor induce renal mitochondrial biogenesis (MB) and that stimulation of the 5-HT1F receptor following ischemia/reperfusion (I/R)-induced acute kidney injury (AKI) accelerated the recovery of renal function in mice. The goal of this study was to examine the contribution of the 5-HT1F receptor in the regulation of renal mitochondrial homeostasis and renal function in naïve and injured mice. Although 5-HT1F receptor knockout (KO) mice were healthy and fertile, and did not exhibit renal dysfunction, renal mitochondrial DNA copy number and mitochondrial fission gene expression increased at 10 wk of age. The 5-HT1F receptor KO mice exhibited greater proximal tubular injury and diminished renal recovery after I/R-induced AKI compared with wild-type mice. These findings were associated with persistent suppression of renal cortical MB and ATP levels after injury. In summary, the 5-HT1F receptor is a component of physiological MB regulation in the kidney, and its absence potentiates renal injury and impedes recovery.

PGC1α promotes cisplatin resistance in human ovarian carcinoma cells through upregulation of mitochondrial biogenesis.

The induction of lesions in nuclear and mitochondrial DNA by cisplatin is only a small component of its cytostatic/cytotoxic activity. The signaling pathway network in the nucleus and cytoplasm may contribute to chemotherapeutic resistance. Peroxisome proliferator-activated receptor-coactivator1α (PGC1α)-mediated mitochondrial biogenesis regulates mitochondrial structural and the functional adaptive response against chemotherapeutic stress, and may be a therapeutic target. However, this regulatory network is complex and depends upon tumor types and environments, which require further investigation. Our previous study found that cisplatin-resistant ovarian epithelial carcinoma was more dependent on mitochondrial aerobic oxidation to support their growth, suggesting the association between mitochondrial function and chemotherapeutic resistance. In the present study, it was demonstrated that the expression of PGC1α and level of mitochondrial biogenesis were higher in cisplatin-resistant SKOV3/DDP cells compared with cisplatin-sensitive SKOV3 cells. Furthermore, SKOV3/DDP cells upregulated the expression of PGC1α and maintained mitochondrial structural and functional integrity through mitochondrial biogenesis under cisplatin stress. Inhibiting the expression of PGC1α using short hairpin RNA led to the downregulation of mitochondrial biogenesis and high levels of apoptosis in the SKOV3/DDP cells, and cisplatin resistance was reversed in the PGC1α-deficient SKOV3/DDP cells. Collectively, the present study provided evidence that cisplatin stimulated the expression of PGC1α and the upregulation of mitochondrial biogenesis through PGC1α, promoting cell viability and inhibiting apoptosis in response to cisplatin treatment, thus triggering cisplatin resistance in ovarian cancer cells.

NONSULFATED SULFAKININ CHANGES METABOLIC PARAMETERS OF INSECT FAT BODY MITOCHONDRIA.

We investigated the effect of neuropeptide, the nonsulfated sulfakinin (SK) Zopat-SK-1 (pETSDDYGHLRFa) on the mitochondrial oxidative metabolism in the Zophobas atratus larval fat body. Mitochondria were isolated from beetle fat bodies 2 and 24 h after hormone injection. The administration of 20 pmol of Zopat-SK-1 to feeding larvae led to decreased mitochondrial oxidative activities in larval fat body. Diminished activities of citrate synthase and the cytochrome pathway, that is, nonphosphorylating and phosphorylating respiration during succinate oxidation, were observed. However, the effect of Zopat-SK-1 was more pronounced in fat body of insects after 24 h since hormone application. In hormone-treated larval fat bodies, mitochondrial respiration was decreased at the level of respiratory chain and the TCA cycle as well as at the level of mitochondrial biogenesis, as indicated by decreased activities of mitochondrial marker enzymes in fat body homogenates. The inhibition of succinate oxidation may indicate the role of Zopat-SK-1 in the regulation of mitochondrial complex II activity. Moreover, decreased respiratory chain activity was accompanied by the reduced activity of mitochondrial energy-dissipating pathway, uncoupling protein 4. The observed decrease in mitochondrial oxidative metabolism may reflect the Zopat-SK-1-induced reduction in the metabolic rate of larval fat body linked to actual energetic demands of animal.

Quercetin reduces obesity-induced hepatosteatosis by enhancing mitochondrial oxidative metabolism via heme oxygenase-1.

BackgroundObesity-induced hepatic lipid accumulation causes lipotoxicity, mitochondrial dysfunction, oxidative stress, and insulin resistance, and is implicated in non-alcoholic hepatic pathologies such as steatohepatitis and fibrosis. Heme oxygenase-1 (HO-1), an important antioxidant enzyme catalyzing the rate-limiting step in heme degradation, protects against oxidative stress, inflammation, and metabolic dysregulation. Here, we demonstrate that the phytochemical, quercetin, a natural polyphenol flavonoid, protects against hepatic steatosis in obese mice fed a high-fat diet, and that it does so by inducing HO-1 and stimulating increased hepatic mitochondrial oxidative metabolism.MethodsMale C57BL/6 mice were fed a regular diet (RD), a high-fat diet (HFD), and an HFD supplemented with quercetin for 9 weeks. Levels of mitochondrial biogenesis and oxidative metabolic transcripts/proteins were measured by real-time PCR and/or Western blotting. HO-1 transcripts/proteins were measured real-time PCR and/or Western blotting.ResultsQuercetin upregulated genes involved in mitochondrial biogenesis and oxidative metabolism in lipid-laden hepatocytes and the livers of HFD-fed obese mice, and this was accompanied by increased levels of the transcription factor, nuclear erythroid 2-related factor 2 (Nrf-2), and HO-1 protein. The HO-1 inducer hemin and the HO-1 byproduct carbon monoxide (CO) also enhanced hepatic oxidative metabolism in HFD-fed obese mice. Moreover, the metabolic changes and the lipid-lowering effects of quercetin were completely blocked by the HO-1 inhibitor ZnPP and by deficiency of Nrf-2.ConclusionThese findings suggest that quercetin stimulates hepatic mitochondrial oxidative metabolism by inducing HO-1 via the Nrf-2 pathway. Quercetin may be useful in protecting against obesity-induced hepatosteatosis.

Regulation and Quantification of Cellular Mitochondrial Morphology and Content

Mitochondria play a key role in signal transduction, redox homeostasis and cell survival, which extends far beyond their classical functioning in ATP production and energy metabolism. In living cells, mitochondrial content ("mitochondrial mass") depends on the cell-controlled balance between mitochondrial biogenesis and degradation. These processes are intricately linked to changes in net mitochondrial morphology and spatiotemporal positioning ("mitochondrial dynamics"), which are governed by mitochondrial fusion, fission and motility. It is becoming increasingly clear that mitochondrial mass and dynamics, as well as its ultrastructure and volume, are mechanistically linked to mitochondrial function and the cell. This means that proper quantification of mitochondrial morphology and content is of prime importance in understanding mitochondrial and cellular physiology in health and disease. This review first presents how cellular mitochondrial content is regulated at the level of mitochondrial biogenesis, degradation and dynamics. Next we discuss how mitochondrial dynamics and content can be analyzed with a special emphasis on quantitative live-cell microscopy strategies.

Resveratrol Alleviates Lung Ischemia and Reperfusion–Induced Pulmonary Capillary Injury Through Modulating Pulmonary Mitochondrial Metabolism

ObjectiveLung ischemia and reperfusion (I/R) injury is one of the major causes of postoperative pulmonary dysfunction after cardiopulmonary surgery and thoracic organ transplantation. Recent studies suggest that lung I/R injury may be associated with defects in pulmonary mitochondrial function, in addition to damage from reactive oxygen species. In this study, we examined effects of one lung I/R injury on the other lung, and the protective efficacy of resveratrol on mitochondrial biogenesis in lungs. MethodsStudies were performed in male Sprague-Dawley rats in 3 groups: sham-operated, lung I/R injury, and treated with resveratrol before lung I/R injury (20 mg/kg/d, orally). Lung ischemia was established by occluding the lung left hilum for 60 minutes, followed by releasing the occlusion and closing the chest. Four days after ischemia, we assessed the lung water content and protein concentration in lung lavage of the nonischemic lung; lung inflammation and pulmonary oxidative stress were assessed by leukocyte counts and tissue content of malondialdehyde (MDA), respectively. The level of mitochondrial biogenesis was determined according to PGC1-α mRNA expression. ResultsThe left lung I/R injury significantly suppressed right lung PGC1-α mRNA expression, increasing pulmonary oxidative stress, lung water content, and lavage leukocyte count and protein concentration (P < .05). Resveratrol treatment attenuated lung injury as well as increasing PGC1-α mRNA expression. ConclusionsResveratrol treatment protects lung against I/R injury through improving mitochondrial biogenesis and reducing oxidative stress and leukocyte infiltration.