Development and validation of cuproptosis-related genes in synovitis during osteoarthritis progress

Copper is an essential cofactor for all organisms, and yet it becomes toxic if concentrations exceed a threshold maintained by evolutionarily conserved homeostatic mechanisms. How excess copper induces cell death, however, is unknown. Here, we show in human cells that copper-dependent, regulated cell death is distinct from known death mechanisms and is dependent on mitochondrial respiration. We show that copper-dependent death occurs by means of direct binding of copper to lipoylated components of the tricarboxylic acid (TCA) cycle. This results in lipoylated protein aggregation and subsequent iron-sulfur cluster protein loss, which leads to proteotoxic stress and ultimately cell death. These findings may explain the need for ancient copper homeostatic mechanisms. Cell death is an essential, finely tuned process that is critical for the removal of damaged and superfluous cells. Multiple forms of programmed and nonprogrammed cell death have been identified, including apoptosis, ferroptosis, and necroptosis. Tsvetkov et al . investigated whether abnormal copper ion elevations may sensitize cells toward a previously unidentified death pathway (see the Perspective by Kahlson and Dixon). By performing CRISPR/Cas9 screens, several genes were identified that could protect against copper-induced cell killing. Using genetically modified cells and a mouse model of a copper overload disorder, the researchers report that excess copper promotes the aggregation of lipoylated proteins and links mitochondrial metabolism to copper-dependent death. —PNK Lipoylation determines sensitivity to copper-induced cell death.

To report the level and trends of prevalence, incidence and years lived with disability (YLDs) for osteoarthritis (OA) in 195 countries and territories from 1990 to 2017 by age, sex and Socio-demographic index (SDI; a composite of sociodemographic factors). Publicly available modelled data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 were used. The burden of OA was estimated for 195 countries and territories from 1990 to 2017, through a systematic analysis of prevalence and incidence modelled data using the methods reported in the GBD 2017 Study. All estimates were presented as counts and age-standardised rates per 100 000 population, with uncertainty intervals (UIs). Globally, the age-standardised point prevalence and annual incidence rate of OA in 2017 were 3754.2 (95% UI 3389.4 to 4187.6) and 181.2 (95% UI 162.6 to 202.4) per 100 000, an increase of 9.3% (95% UI 8% to 10.7%) and 8.2% (95% UI 7.1% to 9.4%) from 1990, respectively. In addition, global age-standardised YLD rate in 2017 was 118.8 (95% UI 59.5 to 236.2), an increase of 9.6% (95% UI 8.3% to 11.1%) from 1990. The global prevalence was higher in women and increased with age, peaking at the >95 age group among women and men in 2017. Generally, a positive association was found between the age-standardised YLD rate and SDI at the regional and national levels. Age-standardised prevalence of OA in 2017 ranged from 2090.3 to 6128.1 cases per 100 000 population. United States (6128.1 (95% UI 5729.3 to 6582.9)), American Samoa (5281 (95% UI 4688 to 5965.9)) and Kuwait (5234.6 (95% UI 4643.2 to 5953.6)) had the three highest levels of age-standardised prevalence. Oman (29.6% (95% UI 24.8% to 34.9%)), Equatorial Guinea (28.6% (95% UI 24.4% to 33.7%)) and the United States 23.2% (95% UI 16.4% to 30.5%)) showed the highest increase in the age-standardised prevalence during 1990–2017. OA is a major public health challenge. While there is remarkable international variation in the prevalence, incidence and YLDs due to OA, the burden is increasing in most countries. It is expected to continue with increased life expectancy and ageing of the global population. Improving population and policy maker awareness of risk factors, including overweight and injury, and the importance and benefits of management of OA, together with providing health services for an increasing number of people living with OA, are recommended for management of the future burden of this condition.

The pyruvate dehydrogenase complexes (PDCs) from all known living organisms comprise three principal catalytic components for their mission: E1 and E2 generate acetyl-coenzyme A, whereas the FAD/NAD(+)-dependent E3 performs redox recycling. Here we compare bacterial (Escherichia coli) and human PDCs, as they represent the two major classes of the superfamily of 2-oxo acid dehydrogenase complexes with different assembly of, and interactions among components. The human PDC is subject to inactivation at E1 by serine phosphorylation by four kinases, an inactivation reversed by the action of two phosphatases. Progress in our understanding of these complexes important in metabolism is reviewed. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.