Background/Objectives: The mitochondrial unfolded protein response (UPRmt) is one of the mitochondrial quality control mechanisms that is responsible for reparation and removal of damaged proteins in mitochondria. Methods: Here we investigated the role of the UPRmt in the myocardium of humans with and without heart failure and in the cell culture model. Results: The analysis of myocardial samples by ELISA from patients with ischemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM), as well as healthy donors, revealed a significantly reduced expression of the UPRmt proteins HSP10, CLPP, LONP1, OMA1, and SPG7 in patients with DCM and ICM. Furthermore, patients with DCM and ICM exhibited elevated levels of myocardial reactive oxygen species (ROS, tested by 4-hydroxynonenal) compared to controls, and a positive correlation between ROS production and mt-HSP70, OMA1, and SPG7 protein expression. The correlation analysis indicated a negative correlation between cardiomyocyte hypertrophy and the expression of several UPRmt genes. The inhibition of four tested UPRmt effector proteins exacerbated the injury of cultured cells under oxidative stress. The patients with ICM, DCM, or both, who showed lower myocardial expression of HSP10, HSP60, HTRA2, OMA1, SPG7, and YME1L, underwent heart transplantation or implantation of a left ventricular assist device earlier in life compared to those with the higher protein expression. Conclusions: In conclusion, our findings indicate that the reduced expression of several UPRmt effector proteins is associated with accelerated heart failure in patients, which, together with other results, indicates that impaired UPRmt may contribute to the pathogenesis of heart failure in humans.

This study was designed to examine the association between myocardial concentrations of the trace elements Cu, Fe, Mn, Mo, and Zn and the expression of mitochondrial unfolded protein response (UPRmt) elements and the age of patients who received heart transplantation or a left-ventricular assist device (ageHTx/LVAD). Inductively coupled plasma mass spectrometry was used to determine the concentration of Cu, Fe, Mn, Mo, and Zn in the myocardium of control subjects and patients undergoing heart transplantation or left-ventricular assist device (LVAD) implantation. We used ELISA to quantify the expression of UPRmt proteins and 4-Hydroxynonenal (4-HNE), which served as a marker of oxidative-stress-induced lipid peroxidation. Concentrations of Cu, Mn, Mo, and Zn were similar in the control and heart failure (HF) myocardium, while Fe showed a significant decrease in the HF group compared to the control. A higher cumulative concentration of Fe and Zn in the myocardium was associated with reduced age_HTx/LVAD, which was not observed for other combinations of trace elements or their individual effects. The trace elements Cu, Mn, and Zn showed positive correlations with several UPRmt proteins, while Fe had a negative correlation with UPRmt effector protease YME1L. None of the trace elements correlated with 4-HNE in the myocardium. The concentrations of the trace elements Mn and Zn were significantly higher in the myocardium of patients with dilated cardiomyopathy than in patients with ischemic cardiomyopathy. A higher cumulative concentration of Fe and Zn in the myocardium was associated with a younger age at which patients received heart transplantation or LVAD, potentially suggesting an acceleration of HF. A positive correlation between myocardial Cu, Mn, and Zn and the expression of UPRmt proteins and a negative correlation between myocardial Fe and YME1L expression suggest that these trace elements exerted their actions on the human heart by interacting with the UPRmt. An altered generation of oxidative stress was not an underlying mechanism of the observed changes.

Background and Objectives: Oral squamous cell carcinoma (OSCC) is characterized by a high propensity for cervical lymph node metastasis, which remains a strong predictor of patient outcome. Despite advances in management, the prognosis for OSCC has not significantly improved, and the identification of reliable predictors for occult lymph node metastasis (OLNM) in clinically node-negative (cN0) patients is crucial for optimizing treatment strategies. Lymphovascular density (LVD) immunohistochemically assessed by podoplanin (D2-40) has been proposed as a potential biomarker for regional metastasis, but its prognostic value remains controversial. This study aimed to evaluate the prognostic significance of intratumoral (ILVD) and peritumoral lymphovascular density (PLVD) for OLNM in OSCC. Materials and Methods: A retrospective analysis was conducted on 43 cN0 patients with primary OSCC who underwent surgical resection and elective neck dissection (END) at a tertiary care cancer center. LVD was assessed by immunohistochemical staining for podoplanin (D2-40) in both intratumoral and peritumoral regions. Clinicopathological data were collected and statistically analyzed. Results: In observed cohort peritumoral LVD was significantly higher than intratumoral LVD. PLVD was also significantly higher in early-stage tumors (pT1/pT2) compared to advanced stages (pT3/pT4). Higher ILVD was significantly associated with the presence of OLNM. Neither ILVD nor PLVD demonstrated a statistically significant influence on overall survival, although a trend toward poorer outcomes was observed in patients with higher ILVD. Conclusions: ILVD was significantly associated with occult nodal metastasis, whereas PLVD was not. However, neither LVD parameter independently predicted overall survival. Results suggest that ILVD may serve as a useful marker for identifying cN0 OSCC patients at higher risk for occult metastasis.