Person:

Shaw, Stanley

Deficiency of mitochondrial complex I is encountered in both rare and common diseases, but we have limited therapeutic options to treat this lesion to the oxidative phosphorylation system (OXPHOS). Idebenone and menadione are redox-active molecules capable of rescuing OXPHOS activity by engaging complex I-independent pathways of entry, often referred to as “complex I bypass.” In the present study, we created a cellular model of complex I deficiency by using CRISPR genome editing to knock out Ndufa9 in mouse myoblasts, and utilized this cell line to develop a high-throughput screening platform for novel complex I bypass factors. We screened a library of ~40,000 natural product extracts and performed bioassay-guided fractionation on a subset of the top scoring hits. We isolated four plant-derived 1,4-naphthoquinone complex I bypass factors with structural similarity to menadione: chimaphilin and 3-chloro-chimaphilin from Chimaphila umbellata and dehydro-α-lapachone and dehydroiso-α-lapachone from Stereospermum euphoroides. We also tested a small number of structurally related naphthoquinones from commercial sources and identified two additional compounds with complex I bypass activity: 2-methoxy-1,4-naphthoquinone and 2-methoxy-3-methyl-1,4,-naphthoquinone. The six novel complex I bypass factors reported here expand this class of molecules and will be useful as tool compounds for investigating complex I disease biology.

Background and aims Accurate assessment of the risk of mortality following a cirrhosis-related admission can enable health-care providers to identify high-risk patients and modify treatment plans to decrease the risk of mortality. Methods: We developed a post-discharge mortality prediction model for patients with a cirrhosis-related admission using a population of 314,292 patients who received care either at Massachusetts General Hospital (MGH) or Brigham and Women’s Hospital (BWH) between 1992 and 2010. We extracted 68 variables from the electronic medical records (EMRs), including demographics, laboratory values, diagnosis codes, and medications. We then used a regularized logistic regression to select the most informative variables and created a risk score that comprises the selected variables. To evaluate the potential for generalizability of our score, we applied it on all cirrhosis-related admissions between 2010 and 2015 at an independent EMR data source of more than 18 million patients, pooled from different health-care systems with EMRs. We calculated the areas under the receiver operating characteristic curves (AUROCs) to assess prediction performance. Results: We identified 4,781 cirrhosis-related admissions at MGH/BWH hospitals, of which 778 resulted in death within 90 days of discharge. Nine variables were the most effective predictors for 90-day mortality, and these included all MELD-Na’s components, as well as albumin, total cholesterol, white blood cell count, age, and length of stay. Applying our nine-variable risk score (denoted as “MELD-Plus”) resulted in an improvement over MELD and MELD-Na scores in several prediction models. On the MGH/BWH 90-day model, MELD-Plus improved the performance of MELD-Na by 11.4% (0.78 [95% CI, 0.75–0.81] versus 0.70 [95% CI, 0.66–0.73]). In the MGH/BWH approximate 1-year model, MELD-Plus improved the performance of MELD-Na by 8.3% (0.78 [95% CI, 0.76–0.79] versus 0.72 [95% CI, 0.71–0.73]). Performance improvement was similar when the novel MELD-Plus risk score was applied to an independent database; when considering 24,042 cirrhosis-related admissions, MELD-Plus improved the performance of MELD-Na by 16.9% (0.69 [95% CI, 0.69–0.70] versus 0.59 [95% CI, 0.58–0.60]). Conclusions: We developed a new risk score, MELD-Plus that accurately stratifies the short-term mortality of patients with established cirrhosis, following a hospital admission. Our findings demonstrate that using a small set of easily accessible structured variables can help identify novel predictors of outcomes in cirrhosis patients and improve the performance of widely used traditional risk scores.