Physiological Importance of Mitochondria: History
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Tanzeel Khan
,
Rashid Waseem
,
Zainy Zehra
,
Ayesha Aiman
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Priyanka Bhardwaj
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Jaoud Ansari
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Md. Imtaiyaz Hassan
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Asimul Islam

Mitochondria are among the most important organelles in eukaryotic cells and have a distinctive structure composed of lipid-bilayer membranes. A mitochondrion has a unique structure comprising four parts: the outer mitochondrial membrane (OMM), the inter-membranous space (IMS), the inner mitochondrial membrane (IMM), and the matrix, with each part performing a specific role. 

  • mitochondrial dysfunction
  • nanoparticles
  • drug delivery

1. Introduction

Mitochondria are among the most important organelles in eukaryotic cells and have a distinctive structure composed of lipid-bilayer membranes [1]. A mitochondrion has a unique structure comprising four parts: the outer mitochondrial membrane (OMM), the inter-membranous space (IMS), the inner mitochondrial membrane (IMM), and the matrix, with each part performing a specific role. The permeability of mitochondrial lipid membranes differs; the outer membrane is permeable to a broad range of small molecules, but the inner membrane is selective [2]. The passage of molecules through the IMM is controlled by a variety of specialized channel proteins [3]. Therefore, compared to the cytoplasm, the mitochondrial matrix has a remarkably different electrochemical potential and composition. Moreover, mitochondria are the only organelles that have their own genomes, i.e., a circular form of DNA with 16,500 circular base pairs and 37 genes. These mitochondrial DNAs (mtDNAs) encode 2 ribosomal RNAs (rRNAs), 13 messenger RNAs (mRNAs), and 22 transfer RNAs (tRNAs), which are all required for the synthesis of 13 proteins that are components of the electron transport chain (ETC) for performing oxidative phosphorylation [4]. Mutations in either mtDNA or nuclear DNA genes coding for mitochondrial proteins may lead to the onset of mitochondrial diseases [5][6]. The identification of mitochondria as an emerging pharmaceutical target has led to the development of several mitochondria-targeting strategies for the effective treatment of diseases associated with mitochondrial dysfunction. Some of the current drugs’ limitations include low solubility, non-selective biodistribution, and poor bioavailability. Nanopreparations have the potential to overcome the present barriers by providing a sustained and targeted medication delivery system to mitochondria. Recently, NPs and traditional chemotherapeutic drugs have been conjugated to create biocompatible, multifunctional mitochondria-targeted nanoplatforms. Furthermore, nanopreparations may also improve therapeutic compounds’ pharmacokinetic characteristics and bio-distribution patterns. This technique is also being utilized to create targeted medicine delivery systems and hybrid nanostructures that can be activated by light (also known as photodynamic and/or photothermal therapy).

2. Physiological Importance of Mitochondria

2.1. Mitochondria and Oxidative Phosphorylation

Mitochondria are implicated in various critical processes in animal cells, such as oxidative phosphorylation (OXPHOS), the tricarboxylic acid (TCA) cycle, fatty-acid oxidation, calcium ion homeostasis in association with the endoplasmic reticulum (ER) [7], amino acid metabolism [8], and the regulation of apoptosis [9]. The production of ATP for energy is the primary function of mitochondria. There are two ways by which cells produce ATP; in the cytosol through glycolysis and in mitochondria by oxidative phosphorylation. Substrates such as pyruvate and fatty acids are oxidized through TCA and β-oxidation pathways, respectively. The by-products of both the processes, flavin adenine dinucleotide (FADH2) and nicotinamide adenine dinucleotide (NADH) are used by the electron transport chain (ETC) of mitochondria to generate ATP. The ETC comprises protein complexes that lie within the inner mitochondrial membrane [10]. The electrons transported by NADH and FADH2 are transferred to complex I (NADH dehydrogenase) and complex II (succinate dehydrogenase) of protein complexes. After that, these electrons are transported by coenzyme Q to complex III (cytochrome bc1) and finally through complex IV (cytochrome c oxidase) to oxygen molecules. This sequential passage of electrons along these protein complexes is accompanied by the generation of a proton gradient across the IMM, which is further utilized by FO F1 ATP synthase in the formation of ATP. Therefore, it is clear that any damage that impairs the mitochondrial capacity to carry out these critical functions will have a significant impact on ATP synthesis that would be detrimental to cellular functioning [11].

2.2. Mitochondria and Reactive Oxygen Species (ROS)

ROS are produced as a consequence of oxygen metabolism, which includes hydrogen peroxide (H2O2), superoxide anions (O2−), and hydroxyl radicals (OH●) [12]. These ROS are mainly generated from oxidative phosphorylation. The primary member of ROS is a superoxide anion (O2−) produced by both complex I and complex III of the ETC [13]. These overproduced superoxide anions are endogenously controlled by superoxide dismutase (SOD) via their conversion into hydrogen peroxide, which in turn is converted into water by catalase or peroxidase enzymes. However, in various diseases such as neurological diseases, cardiovascular disorders, and autoimmune diseases, a disturbance of this redox balance occurs in mitochondria, which activates inflammasomes, RIG-I-like receptors (RLRs), and mitogen-activated protein kinases (MAPK), leading to the activation of innate immune and inflammatory responses [14]. Numerous anti-oxidants such as coenzyme Q10 [15], vitamin E [16], apocynin [17], and SOD mimetic [18] in conjugation with small cationic molecules such as triphenylphosphonium (TPP+) have been used in controlling imbalanced redox species in mitochondria.

2.3. Mitochondria and Calcium Homeostasis

The endoplasmic reticulum in cells is primarily responsible for storing calcium cations; however, mitochondria can also temporarily store calcium [19]. In different kinds of healthy cells, mitochondria can withstand intracellular calcium concentrations between 50 and 500 nM. This buffering capacity is maintained via the calcium uniporter located in the IMM [20]. Ca2+ ions can permeate through the outer mitochondrial membrane; when the Ca2+ ion concentration surpasses a 1 mM concentration in extreme conditions, the calcium uniporter channel opens and transfers Ca2+ ions from the cytosol to the matrix of mitochondria [21]. Calcium homeostasis is important for various metabolic functions. Calcium is intricately involved in synaptic plasticity, organelle movement, and neurotransmitter vesicle release in brain [22]. In cellular signaling pathways, Ca2+ ions are critically involved and balance cellular signaling among cells [23].

2.4. Mitochondria and Apoptosis

A highly controlled type of cell death called apoptosis is managed by mitochondria. It is a crucial process in the development (e.g., in the modeling of limbs and neurodevelopment) and lifelong maintenance of tissue homeostasis. In terms of morphology, cells undergoing apoptosis show membrane blebbing and chromatin condensation. Therefore, apoptosis can also be easily characterized. The mitochondrial pathway (extrinsic) and the death receptor pathway are the two pathways through which apoptosis manifests itself in mammalian cells [24]. The mitochondrial apoptosis pathway can respond to both intracellular and extracellular cues, as exemplified by DNA damage. Cytochrome c, which typically transports electrons between complexes III and IV of the ETC, is the most effective signaling molecule in the apoptotic pathway. In apoptosis, however, cytochrome c release leads to the loss of mitochondrial membrane potential, resulting in the permeabilization of the OMM. This release of cytochrome c from the mitochondrial intermembrane space to the cytosol activates various caspase enzymes that cause apoptosis [25].

2.5. Mitochondria and Fe/S Clusters

The biosynthesis of various protein cofactors, including Moco, heme, lipoic acid, biotin, and iron–sulfur (Fe/S) clusters, is another important function of mitochondria [26]. Among these, Fe/S clusters are of particular importance due to their involvement in electron transfer reactions as well as in catalytic and regulatory processes. Moreover, they also serve as sulfur donors during the synthesis of lipoic acid and biotin. There are many types of Fe/S clusters, but [2Fe-2S] and [4Fe-4S] are the most prevalent and simplest clusters [27]. Mitochondrial Fe–S biosynthesis is initiated by the iron–sulfur cluster (ISC) assembly, which consists of more than 15 components [28]. Apart from mitochondrial Fe/S, this iron–sulfur cluster (ISC) assembly machinery in mitochondria is also required for the biosynthesis of cytosolic Fe/S clusters [29]. In mitochondria, these Fe/S proteins are specifically involved in the TCA cycle (aconitase), fatty acid oxidation (ETF-ubiquinone oxidoreductase), the electron transfer chain (respiratory complexes I–III), and in biotin and lipoate biosynthesis (lipoate and biotin synthases) [29]. Dysfunction in assembly with respect to the formation of Fe/S proteins is linked with severe and frequently fatal neurodegenerative, metabolic, or hematological diseases [30][31].

This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics14122657

References

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