Mitochondria are key players in energy production, critical activity for the smooth functioning of energy-demanding organs such as the muscles, brain, and heart. Therefore, dysregulation or alterations in mitochondrial bioenergetics primarily perturb these organs. Within the cell, mitochondria are the major site of reactive oxygen species (ROS) production through the activity of different enzymes since it is one of the organelles with the major availability of oxygen. ROS can act as signaling molecules in a number of different pathways by modulating calcium (Ca2+) signaling. Interactions among ROS and calcium signaling can be considered bidirectional, with ROS regulating cellular Ca2+ signaling, whereas Ca2+ signaling is essential for ROS production. In particular, we will discuss how alterations in the crosstalk between ROS and Ca2+ can lead to mitochondrial bioenergetics dysfunctions and the consequent damage to tissues at high energy demand, such as the heart. Changes in Ca2+ can induce mitochondrial alterations associated with reduced ATP production and increased production of ROS. These changes in Ca2+ levels and ROS generation completely paralyze cardiac contractility. Thus, ROS can hinder the excitation–contraction coupling, inducing arrhythmias, hypertrophy, apoptosis, or necrosis of cardiac cells. These interplays in the cardiovascular system are the focus of this review.

Pathogenic variants in SPART cause Troyer syndrome, characterized by lower extremity spasticity and weakness, short stature and cognitive impairment, and a severe mitochondrial impairment. Herein, we report the identification of a role of Spartin in nuclear-encoded mitochondrial proteins. SPART biallelic missense variants were detected in a 5-year-old boy with short stature, developmental delay and muscle weakness with impaired walking distance. Patient-derived fibroblasts showed an altered mitochondrial network, decreased mitochondrial respiration, increased mitochondrial reactive oxygen species and altered Ca 2+ versus control cells. We investigated the mitochondrial import of nuclear-encoded proteins in these fibroblasts and in another cell model carrying a SPART loss-of-function mutation. In both cell models the mitochondrial import was impaired, leading to a significant decrease in different proteins, including two key enzymes involved in CoQ10 (CoQ) synthesis, COQ7 and COQ9, with a severe reduction in CoQ content, versus control cells. CoQ supplementation restored cellular ATP levels to the same extent shown by the re-expression of wild-type SPART, suggesting CoQ treatment as a promising therapeutic approach for patients carrying mutations in SPART .

Background: Every year the number of heart transplant recipients increases but the number of patients in the heart transplant waiting list (HTx WL) does not slow down. However, there are no data on those excluded from HTx WL. The aim was to study clinical differences of chronic heart failure (CHF) patients who excluded from a HTx WL and estimate their survival. Methods: We retrospectively analyzed HTx WL data that was collected from 2010 to 2020 and included 280 patients: 47.4±12.8 year-old, male -210 (75%). We estimated the number of excluded patients, causes of the exclusion and patients' clinical characteristics. Data was analyzed by using the SPSS 21.0. Results: During 10-year follow-up 53 patients (class III by NYHA, class 2 UNOS) excluded from HTx WL: 66% (n=35; 55.4±12.5 year-old; n=33male) -improved (group 1), 9% (n=5; 50 [37;56] year-old; male) refused after the inclusion for their personal reasons (group 2) and 25% (n=13; 58 [46;63] year-old; n=12 -male) -due to diagnosed contraindications (group 3). Most common cause of CHF was ischaemic heart disease (49%, 60% and 69%, respectively). Patients excluded from HTx WL due to their improvement in 17 [8;43] days. LVEF were 21 [17;24] %, 13 [10;17] % and 18 [16;28] %, respectively, (p1,2=0.013) and PASP -44±20 mm Hg, 45 [43;47] mm Hg and 59 [40;67] mm Hg, respectively, (p1,2=0.02). VO2peak was <10-12 ml/kg/min. There was a high incidence of pulmonary hypertension (PHT) in the group 3, including irreversible. NT-proBNP levels were 2556 [1698;3680] pg/ml, 9212 [6226;14508] pg/ml and 3054 [1751;4304] pg/ml, respectively, (p1,2=0.005, p2,3=0.03). After the inclusion in HTx WL, patients completed the SF-36 questionnaire and results did not show significant differences between the groups (p>0.05). One year survival after exclusion was 86% in the group 1, 20% -group 2 and 38% -group 3. Two years after the exclusion 2 patients were put back on HTx WL and then successfully underwent heart transplantation. Mortality of excluded individuals was associated with a higher level of PAWP (r=0.72, p=0.01), a low level of venous oxygen saturation of the central venous blood (r=-0.86, p=0.02), heart rate (r=0.61, p=0.03) and QRS width (r=0.52, p=0.04). Conclusion:In 10 years 19% of patients were excluded from HTx WL, most of them due to the improvement and this one had a higher survival. Most of patients excluded due to irreversible PHT but those who decided to refuse had the lower LVEF. Clinical characteristics, except LVEF and right heart failure, were similar between excluded ones.