**1. Introduction**

The adult heart shows the highest metabolic activity of all organs in the human body by consuming 6 kg of ATP every day. It converts chemical energy stored in fatty acids, lactate and glucose into the mechanical energy to pump blood through the body. The heart contains the highest amount of mitochondria of any tissue [1], comprising about 35% of the cardiac myocyte cell volume [2,3]. A total of 95% of the energy demand of the heart is covered by oxidative phosphorylation in the mitochondria. Due to their central role in energy metabolism, a defect in mitochondria endangers the tight homeostasis of energy supply and demand in the heart. An imbalance between available energy and energy demand has been observed in almost all etiologies of heart failure [4]. Mitochondrial dysfunction can have deleterious consequences for the heart physiology and affects many forms of

heart disease [5,6]. Dysfunctional mitochondria in skeletal muscle also impact heart failure and are associated with exercise intolerance [7].

Mitochondria are double membrane-surrounded organelles. The inner mitochondrial membrane forms cristae structures, which harbor the respiratory chain and form independent units of oxidative phosphorylation [8]. The respiratory chain consists of four complexes (complex I–IV), that are involved in the electron transport from NADH or FADH<sup>2</sup> onto molecular oxygen. Electron transport is coupled with proton export across the inner membrane. The corresponding membrane potential is the driving force for the fifth complex, F1Fo-ATP synthase, to produce ATP. The ADP/ATP carrier (ANT) ensures the exchange of ATP and ADP across the inner membrane.

The reducing equivalents, NADH or FADH2, are yielded in the mitochondrial Krebs cycle and NADH is additionally yielded in glycolysis. A high energy demand results in elevated levels of ADP, which accelerates ATP production at the F1Fo-ATP synthase and thus increases the activity of the respiratory chain. To avoid draining of reducing equivalents under conditions of high energy demand, production is increased by a compensatory upregulation of the Krebs cycle. Ca2<sup>+</sup> plays a key role in coupling energy demanding processes of the myofilaments with mitochondrial metabolism. During excitation, a contraction coupling release of cytosolic Ca2<sup>+</sup> from the sarcoplasmic reticulum stimulates energy conversion in myofilaments. Additionally, Ca2<sup>+</sup> is transported from the cytosol into mitochondria by the mitochondrial calcium uniporter (MCU). Mitochondrial Ca2<sup>+</sup> potently activates several mitochondrial dehydrogenases of the Krebs cycle. This direct coupling of cytosolic and mitochondrial signals allows an immediate activation of Krebs cycle flux under conditions of increased workload. Besides their function in energy conversion, mitochondria participate in multiple metabolic pathways, such as the urea cycle, the metabolism of amino acids and lipids, and the biogenesis of heme and iron sulfur clusters. Mitochondria morphology is highly dynamic and maintained by fission and fusion processes. Mitochondrial dynamics are instrumental for many signaling pathways, such as programmed cell death, calcium signaling or innate immune responses. Impaired mitochondrial dynamics promote mitophagy. This mitochondria-specific form of autophagy maintains mitochondrial function which is particularly important for cardiac homeostasis [9].

Most of the key metabolic enzymes of the mitochondria are embedded in the inner membrane. The phospholipid Cardiolipin (CL) is the characteristic lipid of the inner membrane, playing a pivotal role in most mitochondrial metabolic activities. Here, we will discuss how CL is involved in many essential mitochondrial functions including morphology, metabolism and respiration. Defects in the biosynthesis and remodeling of CL have a strong impact on mitochondrial function and particularly affect tissues with a high energetic contribution of mitochondria, such as the heart and neuronal tissue. Diseases with a direct link to CL biosynthesis and remodeling comprise Sengers disease (OMIM 212350), Barth syndrome (OMIM 302060) and Dilated Cardiomyopathy with Ataxia (DCMA, OMIM 610198). Changes in CL levels are also involved in other cardiac modifications including ischemia/reperfusion injury, diabetic cardiomyopathy and the aging heart.
