According to the Third International Consensus Definition of Sepsis and Septic Shock (Sepsis-3), sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection (Singer et al., 2016). Mortality of sepsis has gradually declined over the last few decades with the timely use of antibiotics, fluid resuscitation, and multi-organ supportive therapies (Liu et al., 2022). However, the data for 2017 reported 11 million sepsis-related deaths, accounting for 19.7 % of all global deaths (Rudd et al., 2020). This indicates that sepsis remains a disease with high mortality and a high healthcare burden.
The prevalence of septic cardiomyopathy (SCM) in patients with sepsis is approximately 30–50 %, with a 28-day mortality rate of 30 % (Wu et al., 2023a). SCM is characterized by reduced left ventricular ejection fraction (LVEF) and injured contractility. Systolic dysfunction is characterized by biventricular dilatation, a reversible decrease in LVEF, and a diminished blood pressure response to intravenous fluids. Myocardial depression is often the main cause of death in SCM patients. Multiple mechanisms have been reported to be involved in SCM, including mitochondrial impairment, oxidative stress, complement activation, apoptosis, and autophagy/mitophagy (Wang et al., 2022a). Among the multiple pathogenic mechanisms mentioned above, mitochondrial impairment is one of the most critical factors in SCM since in the heart, abundant adenosine triphosphate (ATP) is mainly produced in mitochondria (Pan et al., 2018a), which plays an important role in maintaining the systolic and diastolic functions of the heart (Pan et al., 2018b). Meanwhile, previous studies have shown that mitochondria are the main targets of injury during the acute phase of sepsis (Lelubre and Vincent, 2018). Therefore, severe mitochondrial impairment during SCM is fatal.
In dealing with mitochondrial impairment, the mitochondrial quality control system (MQC) plays an irreplaceable role. Mitochondria are highly dynamic and plastic networks that maintain their number, morphology, and function through processes such as mitochondrial fission/fusion, mitophagy, and mitochondrial biogenesis, even under challenging conditions such as hypoxia, energy limitation, inflammation, and developmental factors. These biological processes govern the organelle and molecular mitochondrial homeostasis, known as mitochondrial quality control system (Liu et al., 2023). In the MQC system, a number of studies have revealed the relationship between mitochondrial fusion/fission (Wu et al., 2023b, Zhu et al., 2022a, Yu et al., 2019, Shang et al., 2020a) or mitophagy (Shang et al., 2020b, Jiang et al., 2021, Zhu et al., 2023) with SCM, but there are fewer studies related to mitochondrial biogenesis (Xin and Lu, 2020, Li et al., 2021), the role of which is still unclear, and the post-transcriptional mechanisms that regulate mitochondrial biogenesis need to be further investigated, which draws our attention.
The transfer RNAs (tRNAs)-derived small RNAs (tsRNAs) have been shown to be not merely byproducts of random cleavage of tRNAs, but as regulatory small non-coding RNAs in pathophysiologic processes. It is involved in a wide range of biological processes including regulation of gene expression, anti-apoptosis, initial viral reverse transcription, viral replication and cell-to-cell communication by regulating mRNA stability, inhibiting translation initiation and elongation, regulating ribosome biosynthesis and acting as a novel epigenetic factor (Wen et al., 2021). According to the length and cleavage site of the tRNA, tRNAs produce multiple types of tsRNAs. tRNA-derived stress-induced RNA (tiRNA), which are produced by specific cleavage in the anticodon loop of mature tRNAs with 28–36 nts length, and, as the name implies, are associated with a wide range of stresses and are the most important class of tsRNAs (Li et al., 2018). TsRNAs are closely related to cardiovascular diseases, and it has been shown that tsRNAs play an important role in myocardial hypertrophy (Shen et al., 2018), fulminant myocarditis (Wang et al., 2021a), myocardial ischaemia (Liu et al., 2020a), and atherosclerosis (He et al., 2021). Our previous study revealed the expression changes of tsRNAs in SCM for the first time (Yuan et al., 2022). Based on the microarray results, we found that 5’tiRNA-33-CysACA-1 expression was significantly elevated. Therefore, our study aimed to further investigate the role and mechanism of 5’tiRNA-33-CysACA-1 in SCM and to consider whether it could act as a new regulatory molecule of mitochondrial biogenesis at the post-transcriptional level from the perspective of mitochondrial quality control system, thereby affecting the course of SCM.
Our study suggests that 5’tiRNA-33-CysACA-1 expression is elevated in SCM and leads to impaired mitochondrial function in cardiomyocytes. Mechanistically, 5’tiRNA-33-CysACA-1 contributes to the development of SCM by targeting peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), a key molecule for mitochondrial biogenesis, and affecting the stability of PGC-1α mRNA and leading to a hindrance in mitochondrial biogenesis. Our results reveal the relationship between a novel non-coding RNA and mitochondrial biogenesis, providing new ideas for the study of the regulatory mechanism of mitochondrial biogenesis and providing new targets for the diagnosis and treatment of SCM.
