Defective autophagy is implicated in the pathogenesis of nonalcoholic fatty liver diseases (NAFLD) through poorly defined mechanisms. Cardiolipin is a mitochondrial phospholipid required for bioenergetics and mitophagy from yeast to mammals. Here we investigated a role for ALCAT1 in the development of NAFLD. ALCAT1 is a lysocardiolipin acyltransferase that catalyzes pathological cardiolipin remodeling in several aging‐related diseases. We show that the onset of diet‐induced NAFLD caused autophagic arrest in hepatocytes, leading to oxidative stress, mitochondrial dysfunction, and insulin resistance. In contrast, targeted deletion of ALCAT1 in mice prevented the onset of NAFLD. ALCAT1 deficiency also restored mitophagy, mitochondrial architecture, mitochondrial DNA (mtDNA) fidelity, and oxidative phosphorylation. In support of a causative role of the enzyme in a mitochondrial etiology of the disease, hepatic ALCAT1 expression was significantly up‐regulated in mouse models of NAFLD. Conclusion: Forced expression of ALCAT1 in primary hepatocytes led to multiple defects that are highly reminiscent of NAFLD, including steatosis, defective autophagy, and mitochondrial dysfunction, linking pathological cardiolipin remodeling by ALCAT1 to the pathogenesis of NAFLD. (Hepatology 2015;61:486‐496)

Tafazzin (TAZ) is a phospholipid transacylase that catalyzes the remodeling of cardiolipin, a mitochondrial phospholipid required for oxidative phosphorylation. Mutations of TAZ cause Barth syndrome, which is characterized by mitochondrial dysfunction and dilated cardiomyopathy, leading to premature death. However, the molecular mechanisms underlying the cause of mitochondrial dysfunction in Barth syndrome remain poorly understood. Here we investigated the role of TAZ in regulating mitochondrial function and mitophagy. Using primary mouse embryonic fibroblasts (MEFs) with doxycycline-inducible knockdown of Taz, we showed that TAZ deficiency in MEFs caused defective mitophagosome biogenesis, but not other autophagic processes. Consistent with a key role of mitophagy in mitochondria quality control, TAZ deficiency in MEFs also led to impaired oxidative phosphorylation and severe oxidative stress. Together, these findings provide key insights on mitochondrial dysfunction in Barth syndrome, suggesting that pharmacological restoration of mitophagy may provide a novel treatment for this lethal condition.

Cardiolipin (CL) is a mitochondrial signature phospholipid that is required for membrane structure, respiration, dynamics, and mitophagy. Oxidative damage of CL by reactive oxygen species is implicated in the pathogenesis of Parkinson's disease (PD), but the underlying cause remains elusive. This work investigated the role of ALCAT1, an acyltransferase that catalyzes pathological remodeling of CL in various aging‐related diseases, in a mouse model of PD induced by 1‐methyl‐4‐phenyl‐1,2,4,6‐tetrahydropyridine (MPTP). We show that MPTP treatment caused oxidative stress, mtDNA mutations, and mitochondrial dysfunction in the midbrain. In contrast, ablation of the ALCAT1 gene or pharmacological inhibition of ALCAT1 prevented MPTP‐induced neurotoxicity, apoptosis, and motor deficits. ALCAT1 deficiency also mitigated mitochondrial dysfunction by modulating DRP1 translocation to the mitochondria. Moreover, pharmacological inhibition of ALCAT1 significantly improved mitophagy by promoting the recruitment of Parkin to dysfunctional mitochondria. Finally, ALCAT1 expression was upregulated by MPTP and by α‐synucleinopathy, a key hallmark of PD, whereas ALCAT1 deficiency prevented α‐synuclein oligomerization and S‐129 phosphorylation, implicating a key role of ALCAT1 in the etiology of mouse models of PD. Together, these findings identify ALCAT1 as a novel drug target for the treatment of PD.

Rheumatoid arthritis (RA) is a systematical autoimmune disease, characterized by chronic synovial joint inflammation and hurt. Porphyromonas gingivalis(P. gingivalis) can cause life-threatening inflammatory immune responses in humans when the host pathogenic clearance machinery is disordered. Some epidemiological studies have reported that P. gingivalis exposure would increase the prevalence of RA. However, the results remain inconsistent. Therefore, a meta-analysis was done to systematically analyze the relationship between P. gingivalis exposure and the prevalence of rheumatoid arthritis. Database including Cochrane Library, Web of Science, PubMed, and EMBASE were searched for published epidemiological articles assessed the relationship between P. gingivalis and RA. Obtained studies were screened based on the predefined inclusion and exclusion criteria. The overall Odds Ratios (ORs) of incorporated articles were pooled by random-effect model with STATA 15.1 software. The literature search returned a total of 2057 studies. After exclusion, 28 articles were included and analyzed. The pooled ORs showed a significant increase in the risk of RA in individuals with P. gingivalis exposure (OR = 1.86; 95% CI: 1.43-2.43). Subgroup analysis revealed that pooled ORs from populations located in Europe (OR = 2.17; 95% CI: 1.46-3.22) and North America (OR = 2.50; 95% CI: 1.23-5.08) were significantly higher than that from population in Asia (OR = 1.11; 95% CI: 1.03-1.20). Substantial heterogeneity was observed but did not significantly influence the overall outcome. In conclusion, our results indicated P. gingivalis exposure was a risk factor in RA. Prompt diagnosis and management decisions on P. gingivalis antimicrobial therapy would prevent rheumatoid arthritis development and progression.

Obesity promotes the development of nonalcoholic fatty liver diseases (NAFLDs), yet not all obese patients develop NAFLD. The underlying causes for this discrepancy remain elusive. LPGAT1 is an acyltransferase that catalyzes the remodeling of phosphatidylglycerol (PG), a mitochondrial phospholipid implicated in various metabolic diseases. Here, we investigated the role of LPGAT1 in regulating the onset of diet-induced obesity and its related hepatosteatosis because polymorphisms of the LPGAT1 gene promoter were strongly associated with susceptibility to obesity in Pima Indians. Mice with whole-body knockout of LPGAT1 were generated to investigate the role of PG remodeling in NAFLD. LPGAT1 deficiency protected mice from diet-induced obesity, but led to hepatopathy, insulin resistance, and NAFLD as a consequence of oxidative stress, mitochondrial DNA depletion, and mitochondrial dysfunction. This study identified an unexpected role of PG remodeling in obesity, linking mitochondrial dysfunction to NAFLD.

The objectives of this study were to investigated changes in OHRQoL among patients with different classifications of malocclusion during comprehensive orthodontic treatment. Clinical data were collected from 81 patients (aged 15 to 24) who had undergone comprehensive orthodontic treatment. Participants were classified 3 groups: Class I (n = 35), II (n = 32) and III (n = 14) by Angle classification. OHRQoL was assessed using the Oral Health Impact Profile (OHIP-14). All subjects were examined and interviewed at baseline (T0), after alignment and leveling (T1), after correction of molar relationship and space closure (T2), after finishing (T3). Friedman 2-way analysis of variance (ANOVA) and Wilcoxon signed rank tests were used to compare the relative changes of OHRQoL among the different time points. A Bonferroni correction with P < 0.005 was used to declare significance. Significant reductions were observed in all seven OHIP-14 domains of three groups except for social disability (P > 0.005) in class I and class II, Handicap in class II and class III (P > 0.005). Class I patients showed significant changes for psychological disability and psychological discomfort domain at T1, functional limitation, physical pain at T2. Class III patients showed a significant benefit in all domains except physical pain and functional limitation. Class II patients showed significant changes in the physical pain, functional disability, and physical disability domains at T1. The impact of comprehensive orthodontic treatment on patients’ OHRQoL do not follow the same pattern among patients with different malocclusion. Class II patients benefits the most from the stage of space closure, while class I patients benefits the first stage (alignment and leveling) of treatment in psychological disability and psychological discomfort domains.