**Author details**

the intrinsic function of the cardiomyocytes [157, 158], such as finding ways to increase/restore

Since disruption of metabolic signaling pathways such as in FAO, glucose utilization, or ATP generation contributes to the development of heart dysfunction, proteins in these metabolic pathways have become attractive targets of novel therapeutic strategies for the prevention or early treatment of HF [159]. Selective agonists for each of the PPARs have been established and are currently used to treat hyperlipidemia (fibrates) and diabetes (thiazolidinediones). It must be noted that stimulation of the PPAR pathway in the heart or extra cardiac tissues, e.g., adipose or hepatic tissue, potentially diminishes cardiac lipotoxicity by reducing lipid delivery or increasing mitochondrial oxidation. However, chronic activation of PPARα could lead to deleterious effects, particularly in the context of diabetes, hyperlipidemic states, or the ischemic heart [159]. Additionally, although the molecular mechanisms responsible for mitochondria-mediated disease processes are not yet clear, oxidative stress seems to play an important role. Accordingly, strategies for the targeted delivery of antioxidants to mitochondria are being developed. A typical "mitochondrial cocktail," which may include coenzyme Q10 (CoQ10), creatine, L-carnitine, thiamine, riboflavin, folate, as well as other antioxidants such as vitamins C and E, has been reported to partially improve clinical manifestations, though others have disputed its effectiveness [160]. Although, L-carnitine supplementation may be highly effective in patients diagnosed with DCM secondary to primary systemic carnitine deficiency, supplementation has little effect on other types of mitochondrial cardiomyopathy [132]. Recent developments in mitochondrial-targeted antioxidants that concentrate on the matrix-facing surface of the IMM protect against mitochondrial oxidative damage and hold therapeutic potential for future

Because a cure for mitochondrial genetic defects is still not available, the management of genetic MD with presentation of cardiac pathology, β-blockers, ACE inhibitors, or angiotensin receptor blockers should be administered [146]. Providing rudimentary nutritional education along with nutritional assessment and exercise will be important for the patients to take preventative measures from further lifestyle disease complications [146, 162]. Should there be advanced second- and third-degree AV block coupled with neuromuscular disorders, a permanent pacemaker is highly recommended [163]. Depending on the severity of the mitochondrial cardiomyopathy, cardiac transplantation could be recommended depending on the presence of neuromuscular weakness as it can complicate anesthesia administration [164].

Because diagnosing MD can be challenging for clinicians, research is needed to better understand the complex bioenergetic arrangements and redox networks of the mitochondrion in cardiac cell. Improved understanding of mitochondrial mechanism in the pathophysiology in the heart will help the discovery of novel biomarkers and clinical diagnostic standards for the heart disease. In addition, current pharmacologic strategies are incompletely effective, and large randomized controlled trials are warranted to direct future therapy. Since HF is recognized as a state of myocyte energy starvation, greater evidence, in the form of large randomized, controlled trials, is required to confirm the role of metabolic-modulating drugs in the treatment of HF, which

the energy supply, in addition to reducing the energy demand of the heart [1].

treatment of cardiovascular diseases (CVDs) [161].

**5. Future direction**

48 Mitochondrial Diseases

Shaunrick Stoll, Christiana Leimena and Hongyu Qiu\*

\*Address all correspondence to: hqiu@llu.edu

Division of Physiology, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, USA
