Powering down the mitochondrial LonP1 protease: a novel strategy for anticancer therapeutics.

INTRODUCTION: Mitochondrial LonP1 is an ATP-powered protease that also functions as an ATP-dependent chaperone. LonP1 plays a pivotal role in regulating mitochondrial proteostasis, metabolism and cell stress responses. Cancer cells exploit the functions of LonP1 to combat oncogenic stressors such as hypoxia, proteotoxicity, and oxidative stress, and to reprogram energy metabolism enabling cancer cell proliferation, chemoresistance, and metastasis. AREAS COVERED: LonP1 has emerged as a potential target for anti-cancer therapeutics. We review how cytoprotective functions of LonP1 can be leveraged by cancer cells to support oncogenic growth, proliferation, and survival. We also offer insights into small molecule inhibitors that target LonP1 by two distinct mechanisms: competitive inhibition of its protease activity and allosteric inhibition of its ATPase activity, both of which are crucial for its protease and chaperone functions. EXPERT OPINION: We highlight advantages of identifying specific, high-affinity allosteric inhibitors blocking the ATPase activity of LonP1. The future discovery of such inhibitors has potential application either alone or in conjunction with other anticancer agents, presenting an innovative approach and target for cancer therapeutics.

Child Neurology: Progressive Cerebellar Atrophy and Retinal Dystrophy: Clues to an Ultrarare ACO2-Related Neurometabolic Diagnosis.

Pathogenic biallelic variants in ACO2, which encodes the enzyme mitochondrial aconitase, are associated with the very rare diagnosis of ACO2-related infantile cerebellar retinal degeneration (OMIM 614559). We describe the diagnostic odyssey of a 4-year-old female patient with profound global developmental delays, microcephaly, severe hypotonia, retinal dystrophy, seizures, and progressive cerebellar atrophy. Whole-exome sequencing revealed 2 variants in ACO2; c.2105_2106delAG (p.Gln702ArgfsX9), a likely pathogenic variant, and c.988C>T (p.Pro330Ser) which was classified as a variant of uncertain significance (VUS). While the VUS was confirmed to be maternally inherited, the phase of the other variant could not be confirmed due to lack of a paternal sample. Functional biochemical studies were performed on a research basis to clarify the interpretation of the VUS, which enabled clinical confirmation of the diagnosis of ACO2-related infantile cerebellar retinal degeneration for our patient.

Reduced Liver-Specific PGC1a Increases Susceptibility for Short-Term Diet-Induced Weight Gain in Male Mice.

The central integration of peripheral neural signals is one mechanism by which systemic energy homeostasis is regulated. Previously, increased acute food intake following the chemical reduction of hepatic fatty acid oxidation and ATP levels was prevented by common hepatic branch vagotomy (HBV). However, possible offsite actions of the chemical compounds confound the precise role of liver energy metabolism. Herein, we used a hepatocyte PGC1a heterozygous (LPGC1a) mouse model, with associated reductions in mitochondrial fatty acid oxidation and respiratory capacity, to assess the role of liver energy metabolism in systemic energy homeostasis. LPGC1a male, but not female, mice had a 70% greater high-fat/high-sucrose (HFHS) diet-induced weight gain compared to wildtype (WT) mice (p < 0.05). The greater weight gain was associated with altered feeding behavior and lower activity energy expenditure during the HFHS diet in LPGC1a males. WT and LPGC1a mice underwent sham surgery or HBV to assess whether vagal signaling was involved in the HFHS-induced weight gain of male LPGC1a mice. HBV increased HFHS-induced weight gain (85%, p < 0.05) in male WT mice, but not LPGC1a mice. These data demonstrate a sex-specific role of reduced liver energy metabolism in acute diet-induced weight gain, and the need for a more nuanced assessment of the role of vagal signaling in short-term diet-induced weight gain.

Difference in Housing Temperature-Induced Energy Expenditure Elicits Sex-Specific Diet-Induced Metabolic Adaptations in Mice.

OBJECTIVE: The aim of this study was to test whether increased energy expenditure (EE), independent of physical activity, reduces acute diet-induced weight gain through tighter coupling of energy intake to energy demand and enhanced metabolic adaptations. METHODS: Indirect calorimetry and quantitative magnetic resonance imaging were used to assess energy metabolism and body composition during 7-day high-fat/high-sucrose (HFHS) feeding in male and female mice housed at divergent temperatures (20°C vs. 30°C). RESULTS: As previously observed, 30°C housing resulted in lower total EE and energy intake compared with 20°C mice regardless of sex. Interestingly, housing temperature did not impact HFHS-induced weight gain in females, whereas 30°C male mice gained more weight than 20°C males. Energy intake coupling to EE during HFHS feeding was greater in 20°C versus 30°C housing, with females greater at both temperatures. Fat mass gain was greater in 30°C mice compared with 20°C mice, whereas females gained less fat mass than males. Strikingly, female 20°C mice gained considerably more fat-free mass than 30°C mice. Reduced fat mass gain was associated with greater metabolic flexibility to HFHS, whereas fat-free mass gain was associated with diet-induced adaptive thermogenesis. CONCLUSIONS: These data reveal that EE and sex interact to impact energy homeostasis and metabolic adaptation to acute HFHS feeding, altering weight gain and body composition change.

Reestablishment of Lymphatic Drainage after Vascularized Lymph Node Transfer in a Rat Model.

BACKGROUND: Vascularized lymph node transfer has recently received attention as a potential surgical treatment for lymphedema. Despite good results in some series, the mechanism and benefits of vascularized lymph node transfer have yet to be fully understood. This study aimed to investigate the reestablishment of drainage into transferred lymph nodes following vascularized lymph node transfer in a rat model. METHODS: Seven rats underwent vascularized lymph node transfer. The operation performed on each rat consisted of two parts. First, the left groin lymph node basin with superficial epigastric vessels was harvested as a free flap. Second, the flap was reattached in the left groin of the rat by means of end-to-end microvascular anastomoses. Anastomosis patency was assessed immediately postoperatively and at the time of animal sacrifice. The rats were evaluated for reestablishment of lymphatic flow into the transplanted nodes at 1-month intervals for at least 6 months postoperatively. This was accomplished noninvasively by injecting the rats in their flanks with fluorescent indocyanine green, which was detected using a Photodynamic Eye infrared camera. RESULTS: Anastomoses were patent in all seven rats immediately postoperatively. No indocyanine green uptake was seen in the transplanted lymph node basins in the first 2 months postoperatively in any of the rats. In five of seven rats, however, indocyanine green uptake was demonstrated in the transplanted lymph node basin by 6 months (average, 13 weeks). CONCLUSION: The authors report uptake of indocyanine green in five of seven rats at an average of 13 weeks after lymph node transplantation, consistent with the reestablishment of lymphatic drainage into the transplanted nodes.

Histological Changes in the Rat Femoral Artery Following the Use of the Empty-and-Refill Test.

BACKGROUND: This study examines the effects of the empty-and-refill patency test on rat femoral arteries in the longer postoperative time period. METHODS: A simple arterial anastomosis was performed bilaterally on 20 rats. The empty-and-refill test was performed unilaterally in all rats, leaving the contralateral artery as an internal control. Rats were divided into two cohorts of 10 rats and survived for 48 hours and 2 weeks. Vessel patency was assessed prior to closing and immediately prior to sacrifice. The femoral arteries were harvested bilaterally and hematoxylin and eosin stains were performed. The femoral artery distal to the anastomosis in the region of the empty-and-refill test was histologically evaluated. RESULTS: All vessels were patent at the time of sacrifice. There was no statistical difference in the numeric scoring between the experimental and control vessels in the 48-hour cohort. Almost all vessels harvested at 48 hours showed endothelial cell loss distal to the anastomosis regardless of whether they underwent the empty-and-refill test. The only statistically significant difference in the 2-week cohort was an increase in adventitial smooth muscle proliferation in the experimental group. There were no other statistically significant results between the experimental and control groups at 2 weeks. An overall comparison of both cohorts revealed a statistically significant increase in endothelial cell number and intimal proliferation by 2 weeks postsurgery. CONCLUSION: The empty-and-refill test does not compromise rat femoral artery anastomotic patency, nor does it produce histological damage either 48 hours or 2 weeks postsurgery.