The iAAA-mitochondrial protease YME1L1 regulates the degradation of the short-lived mitochondrial transporter SLC25A38.

Mitochondrial transporters facilitate the exchange of diverse metabolic intermediates across the inner mitochondrial membrane, ensuring an adequate supply of substrates and cofactors to support redox and biosynthetic reactions within the mitochondrial matrix. However, the regulatory mechanisms governing the abundance of these transporters, crucial for maintaining metabolic compartmentalization and mitochondrial functions, remain poorly defined. Through analysis of protein half-life data and mRNA-protein correlations, we identified SLC25A38, a mitochondrial glycine transporter, as a short- lived protein with a half-life of 4 hours under steady-state conditions. Pharmacological inhibition and genetic depletion of various cellular proteolytic systems revealed that SLC25A38 is rapidly degraded by the iAAA-mitochondrial protease YME1L1. Depolarization of the mitochondrial membrane potential induced by the mitochondrial uncoupler carbonyl cyanide m-chlorophenylhydrozone prevented the degradation of SLC25A38. This dual regulation of SLC25A38 abundance by YME1L1 and mitochondrial membrane potential suggests a link between SLC25A38 turnover, the integrity of the inner mitochondrial membrane, and electron transport chain function. These findings open avenues for investigating whether mitochondrial glycine import coordinates with mitochondrial bioenergetics.

Biochemical Safety of SBRT to Multiple Intrahepatic Lesions for Hepatocellular Carcinoma.

Background: We aim to better characterize stereotactic body radiation therapy (SBRT)-related hepatic biochemical toxicity in patients with multiple intrahepatic lesions from hepatocellular carcinoma (HCC). Methods: We conducted a retrospective analysis of patients with HCC who underwent SBRT for 2 or more synchronous or metachronous liver lesions. We collected patient characteristics and dosimetric data (mean liver dose [MLD], cumulative effective volume [Veff], cumulative volume of liver receiving 15 Gy [V15Gy], and cumulative planning target volume [PTV]) along with liver-related toxicity (measured by albumin-bilirubin [ALBI] and Child-Pugh [CP] scores). A linear mixed-effects model was used to assess the effect of multi-target SBRT on changes in ALBI. Results: There were 25 patients and 56 lesions with median follow-up of 29 months. Eleven patients had synchronous lesions, and 14 had recurrent lesions treated with separate SBRT courses. Among those receiving multiple SBRT courses, there were 7 lesions with overlap of V15Gy (median V15Gy overlap: 35 mL, range: 0.5-388 mL). There was no association between cumulative MLD, Veff, V15Gy, or PTV and change in ALBI. Four of 25 patients experienced non-classic radiation-induced liver disease (RILD), due to an increase of CP score by ≥2 points 3 to 6 months after SBRT. Sixteen of 25 patients experienced an increase in ALBI grade by 1 or more points 3 to 6 months after SBRT. Comparing the groups that received SBRT in a single course versus multiple courses revealed no statistically significant differences in liver toxicity. Conclusion: Liver SBRT for multiple lesions in a single or in separate courses is feasible and with acceptable risk of hepatotoxicity. Prospective studies with a larger cohort are needed to better characterize safety in this population.