Mitochondria are important for many cellular processes, such as calcium homeostasis, lipid metabolism, and redox regulation. They make almost all of the ATP needed to keep the heart beating. In a healthy heart, mitochondria are in a continuous state of fusion and fission, which allows cardiac myocytes to adjust to changes in the metabolic demand of the heart. When mitochondria fuse, they form elongated, interconnected networks that make metabolism more efficient. When they separate, they make smaller, fragmented organelles. Fission is a normal physiological process; however, excessive fragmentation of mitochondria is often a sign of pathology and primes them for selective removal by mitophagy. Consequently, cardiac stresses that disturb mitochondrial homeostasis might alter the equilibrium of mitochondrial dynamics, triggering maladaptive remodeling pathways that facilitate the onset and progression of cardiomyopathies [5, 6] and heart failure [7].

Diabetes mellitus and obesity are two examples of metabolic diseases that illustrate this principle quite well. Diabetic cardiomyopathy (DCM) is characterized by severe metabolic disturbances, with mitochondrial dysfunction believed to be a key pathogenic factor. Impaired insulin production or insulin resistance, characteristic of type 1 and type 2 diabetes, respectively, facilitates a transition in the metabolic substrate from glucose toward fatty acid oxidation. This change in metabolism causes mitochondrial dysfunction and lipotoxicity, which have significant impacts on cardiac health and drive the progression of heart disease. A key characteristic of mitochondrial dysfunction in DCM is increased oxidative stress due to excessive mitochondrial ROS generation [8]. ROS not only harm mitochondrial components, but they also change the intracellullar environment by oxidizing protein and lipids. Overexpression of the mitochondrial antioxidant enzyme manganese superoxide dismutase has been demonstrated to enhance cardiac function in diabetic mouse models, underscoring the pathogenic role of ROS in DCM. Increased oxidative stress also causes cardiac myocyte apoptosis, which has been reported to increase by up to 85-fold in diabetic hearts. This leads to the loss of cardiomyocytes, myocardial fibrosis, and adverse cardiac remodeling [9].

Mitophagy is a type of autophagy that only removes damaged mitochondria. It is an important quality-control mechanism. Tight control of mitophagy is important because when mitochondrial turnover is altered cells become stressed and change their morphology. Significantly, recent findings indicate that both inadequate and excessive mitophagy can adversely affect cardiac function, and that the impact of mitophagy dysregulation may differ based on the specific disease context [10].

Mitochondrial dysfunction is also widely acknowledged as a primary driver of ICM. During ischemia, reduced oxygen and nutrient supply hinder mitochondrial ATP synthesis while facilitating ROS production. The quick influx of oxygen and calcium into cardiomyocytes during reperfusion causes the mitochondrial permeability transition pore (mPTP) to open. The opening of the mPTP, along with unchecked ROS generation, leads to the death of cardiac myocytes and exacerbates myocardial scarring. Therapeutic approaches designed to impede mPTP opening or eliminate ROS during reperfusion have demonstrated limited effectiveness in reducing infarct size and enhancing cardiac function in animal models [11]. Mitophagy is also thought to play a role in the development of ICM, but its role seems to depend on the phase. Mitophagy activation may confer protection during ischemia by eliminating damaged mitochondria; nonetheless, it may prove detrimental upon reperfusion, although this remains the subject of debate [12].

Li et al. [4] show that HOXB5 acts as an important upstream regulator of Sirt5, thereby creating a protective signaling axis that preserves the mitochondrial homeostasis during myocardial I/R injury. They utilized an in vitro hypoxia/reoxygenation (H/R) model with H9c2 cardiac myoblasts and an in vivo rodent model of myocardial I/R injury. HOXB5 belongs to the HOX family of transcription factors, which are well known for their roles in embryonic development, hematopoiesis, and cancer [13]. In a prior study, the same research group was the first to associate HOXB5 with mitochondrial control during I/R injury [14]. HOXB5 acts as a transcriptional activator of Sirt5, a mitochondrial NAD⁺-dependent deacylase, that has been associated with mitochondrial regulation during I/R injury [15].

The authors observed a substantial reduction in HOXB5 expression following myocardial I/R injury in rats, particularly within the infarct border zone, which correlates with extensive cardiac myocyte apoptosis. To elucidate a mechanistic relationship between HOXB5 and cardiac protection, HOXB5 was overexpressed in the H9c2 H/R model. Overexpression of HOXB5 greatly reduced apoptosis and mitochondrial oxidative stress in the mitochondria caused by H/R, implicating HOXB5 an important regulator of mitochondrial integrity and cell survival. Further studies demonstrated that HOXB5 inhibited ferroptosis, a regulated form of cell death induced by iron-dependent lipid peroxidation. In line with the idea that excessive mitochondrial fission is detrimental during reperfusion, H/R caused mitochondrial fragmentation and enhanced mitophagy, as shown by alterations in LC3-II expression. Interestingly, overexpression of HOXB5 essentially reversed these effects.

To clarify the downstream mediators of HOXB5 action, Li et al. [4] identified Sirt5 as a direct transcriptional target of HOXB5, corroborating previous bioinformatic predictions. Inhibition of Sirt5 in the H/R model negated the protective effects provided by HOXB5 overexpression, indicating that Sirt5 is crucial for HOXB5-mediated protection. These results identify Sirt5 as an essential regulator of mitochondrial dynamics, energy metabolism, and ferroptotic cell death.

The authors further validated these findings in an in vivo rat model of cardiac I/R injury. Knockdown of Sirt5 worsened cardiac dysfunction, infarct size, inflammation, oxidative stress, ferroptosis, and aberrant mitochondrial dynamics after I/R injury. On the other hand, overexpression of either HOXB5 or Sirt5 improved these pathological outcomes. Importantly, silencing Sirt5 negated the cardioprotective effects of HOXB5, even with increased HOXB5 expression, conclusively demonstrating that HOXB5 mediates its cardioprotective effects predominantly via the control of Sirt5. These findings collectively identified the HOXB5–Sirt5 signaling axis as a major endogenous defense mechanism against myocardial I/R injury.