MITOCHONDRIAL DYNAMICS, ULTRASTRUCTURE AND FUNCTIONS OF MITOCHONDRIA IN HEPATOCYTES: CURRENT CONCEPTS

SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 11 NOVEMBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 55 MITOCHONDRIAL DYNAMICS, ULTRASTRUCTURE AND FUNCTIONS OF MITOCHONDRIA IN HEPATOCYTES: CURRENT CONCEPTS O.M. Nazrullaeva Bukhara State Medical Institute https://doi.org/10.5281/zenodo.17744583 Abstract. Mitochondria are highly organized and dynamic organelles that play a central role in the metabolic and energetic homeostasis of hepatocytes. Recent findings demonstrate that hepatocytes contain thousands of mitochondria interconnected into a functional network that supports oxidative phosphorylation, β-oxidation of fatty acids, detoxification, and metabolite synthesis. Disruption of mitochondrial dynamics—imbalance between fission and fusion—leads to structural disorganization, loss of membrane potential, and activation of apoptosis. The mitophagy system, particularly the PINK1/Parkin pathway, serves as a key quality-control mechanism ensuring the removal of damaged mitochondria and maintaining cellular homeostasis. This review summarizes modern concepts of mitochondrial structure, function, and pathophysiological regulation in hepatocytes based on experimental and clinical data from 2018– 2025. Keywords: mitochondria, hepatocytes, mitophagy, PINK1/Parkin, mitochondrial dynamics, oxidative stress, MASLD, liver. Introduction. Mitochondria are unique organelles possessing a double membrane and their own genetic apparatus, representing a central component of cellular energy and metabolic homeostasis. Since their discovery by R. Altmann in 1890 and subsequent detailed study by C. Benda in the early 20th century, mitochondria were primarily regarded as cellular powerhouses. However, in recent decades, it has become evident that their functions are significantly broader, encompassing participation in signaling cascades, apoptosis, regulation of calcium metabolism, and detoxification reactions [1, 2]. Mitochondria hold a special place in liver cells. The hepatocyte is one of the most metabolically active cells in the body, with mitochondria accounting for up to 18–20% of the cytoplasmic volume. A single hepatocyte contains between 800 and 2000 mitochondria, forming a functionally integrated network that ensures the synthesis of adenosine triphosphate (ATP) through oxidative phosphorylation, β-oxidation of fatty acids, the tricarboxylic acid (TCA) cycle, the urea cycle, and participation in lipid metabolism [3, 4]. This abundance of mitochondria reflects the colossal energy demands of the liver, which performs over 500 biochemical functions—from the synthesis of plasma proteins to the detoxification of xenobiotics and ammonia. Research Goal. Comprehensive analysis of current concepts (2018–2025) regarding the morphofunctional organization, dynamics, mitophagy, and pathophysiological alterations of mitochondria in hepatocytes under normal and various pathological conditions, based on literature and experimental data. Research Objectives. - To systematize data on the ultrastructural and biochemical characteristics of mitochondria in hepatocytes. SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 11 NOVEMBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 56 - To elucidate the mechanisms of mitochondrial dynamics (fusion and fission) and their regulation by key proteins MFN1/2, OPA1, DRP1, and FIS1. - To analyze the role of mitophagy, including the PINK1/Parkin pathway and receptormediated pathways (BNIP3/NIX, FUNDC1), in mitochondrial quality control. - To examine the significance of mitochondria-associated membranes (MAMs) and Ca²⁺ homeostasis in hepatic energy metabolism. - To highlight the involvement of mitochondria in the pathogenesis of MASLD, alcoholic and drug-induced hepatitis, as well as liver fibrosis. - To present contemporary morphofunctional and molecular approaches for assessing mitochondrial alterations. - To summarize promising therapeutic strategies aimed at restoring mitochondrial function and antioxidant defense in hepatocytes. 1. Evolutionary Origin and Structural Organization of Mitochondria. According to the endosymbiotic theory, mitochondria originated from α-proteobacteria that entered into a symbiotic relationship with the ancestors of eukaryotic cells. This explains the presence of their own circular DNA, bacteria-like ribosomes, and a double membrane in mitochondria [5]. In hepatocytes, mitochondria are 0.5–2 µm in length and consist of outer and inner membranes, an intermembrane space, and a matrix. The inner membrane forms numerous invaginations—cristae—which increase the surface area for housing the protein complexes of the electron transport chain (Complexes I– V) and ATP synthase. The matrix contains enzymes for the Krebs cycle, β-oxidation of fatty acids, amino acid metabolism, and enzymes responsible for urea synthesis. The inner membrane contains transport proteins involved in forming the electrochemical gradient (Δψm), essential for ATP synthesis [6]. The structural organization of mitochondria is dynamic: the shape, quantity, and topography of the organelles depend on the functional state of the hepatocyte, the phase of metabolic activity, and the level of oxidative stress. 2. Mitochondrial Dynamics: Fusion, Fission, and Morphofunctional Plasticity. Mitochondria are not static structures but elements of a dynamic network, constantly undergoing processes of fusion and fission. These opposing processes maintain a balance between organelle biogenesis and degradation, enabling the adaptation of the mitochondrial population to the cell's metabolic demands [7]. The process of mitochondrial fusion is regulated by mitofusins 1 and 2 (MFN1, MFN2), located on the outer membrane, and the protein OPA1, localized to the inner membrane [8]. MFN1 and MFN2 facilitate the contact and subsequent merging of the outer membranes of adjacent mitochondria, while OPA1 and cardiolipin mediate the fusion of inner membranes. Such unification promotes the exchange of mitochondrial DNA, metabolites, and enzymes, thereby preventing the accumulation of defective organelles and preserving the functional integrity of the network. Mitochondrial division is initiated by the protein DRP1 (Dynamin-related protein 1), which is recruited from the cytosol to the outer membrane, where it interacts with adapter proteins FIS1, MFF, MiD49/51 [9]. DRP1 forms ring-like structures that constrict the mitochondrion, dividing it into two daughter organelles. This process is necessary for the distribution of mitochondria during cell division, the removal of damaged sections, and the renewal of the mitochondrial pool. An imbalance between fission and fusion underlies many pathological conditions. Excessive fission leads to fragmented mitochondria, loss of membrane potential, and impaired ATP synthesis, whereas excessive fusion results in the formation of giant, immobile structures, reduced plasticity, and impaired mitophagy efficiency [10]. For the liver, SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 11 NOVEMBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 57 where energy regulation is particularly sensitive, such disturbances manifest in the development of steatosis, inflammation, and fibrosis. 3. Mitophagy and Mitochondrial Quality Control. Mitochondrial quality control is implemented through mitophagy—a specialized form of autophagy aimed at removing damaged organelles. The classical mitophagy pathway involves the proteins PINK1 (PTEN-induced kinase 1) and Parkin (an E3 ubiquitin ligase) [11]. Under normal conditions, PINK1 is imported into the inner membrane and degraded. Upon the loss of membrane potential (Δψm), import is disrupted, PINK1 accumulates on the outer membrane, and phosphorylates ubiquitin and Parkin, triggering a chain reaction of ubiquitination of outer mitochondrial membrane proteins (MFN1/2, VDAC, Miro, etc.) [12]. These tags are recognized by autophagosome receptors, and defective mitochondria are targeted to lysosomes for degradation. Besides the classical PINK1/Parkin pathway, hepatocytes employ receptor-dependent mitophagy mechanisms mediated by the proteins BNIP3, NIX, and FUNDC1, which are activated under hypoxia or inflammation [13]. Impairment of these processes leads to the accumulation of damaged mitochondria, increased production of reactive oxygen species (ROS), and the initiation of inflammatory responses. In experimental models of non-alcoholic fatty liver disease (MASLD), decreased expression of PINK1 and Parkin has been observed, accompanied by impaired mitophagy and enhanced hepatocyte apoptosis [14]. Conversely, pharmacological activation of mitophagy (e.g., by resveratrol, metformin, berberine) suppresses oxidative stress and restores mitochondrial balance [15]. 4. Mitochondrial Oxidative Stress and Antioxidant Defense. Mitochondria are the primary source of reactive oxygen species (ROS), generated as a byproduct of the electron transport chain. Under normal functioning, 1–2% of electrons passing through Complexes I and III are lost and reduce oxygen to the superoxide anion (O₂⁻). In healthy hepatocytes, ROS are neutralized by the antioxidant defense system: superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), as well as non-enzymatic components—glutathione (GSH), coenzyme Q, and vitamins E, C, and β-carotene [16]. However, under metabolic overload, hypoxia, exposure to toxins, and cytokines, ROS production increases dramatically. This induces the opening of the mitochondrial permeability transition pore (mPTP), mitochondrial swelling, loss of membrane potential, and release of cytochrome C into the cytosol, which activates caspases and apoptosis [17, 18]. It has been proven that oxidative stress is a universal mechanism of hepatocyte damage in non-alcoholic fatty liver disease (MASLD), alcoholic intoxication, and drug-induced liver injury [19]. In this context, an excess of free fatty acids and acetaldehyde enhances electron leak in the respiratory chain, while impaired β-oxidation promotes the accumulation of toxic lipid intermediates—diacylglycerols and ceramides [20]. Mitochondrial enzymes cytochrome P450 2E1 (CYP2E1) and NADPH oxidases (NOX1/4) become additional sources of ROS, amplifying lipid peroxidation and protein damage [21]. Consequently, a vicious cycle forms: mitochondrial damage → increased ROS → activation of inflammation and fibrogenesis. The liver's antioxidant system can partially compensate for these effects. Recent studies show that increased expression of SOD2, GPx-1, and enzymes of the glutathione pathway correlates with reduced fibrosis severity [22]. Mitochondrial deacetylases SIRT3 and SIRT5 deacetylate antioxidant enzymes, enhancing their activity and stabilizing energy metabolism [23]. Thus, maintaining redox homeostasis is a key direction for preventing mitochondrial dysfunction in the liver. SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 11 NOVEMBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 58 5. Mitochondria-Associated Membranes (MAMs) and Ca²⁺ Homeostasis. Modern research confirms that mitochondria closely interact with the endoplasmic reticulum (ER) through specialized regions—mitochondria-associated membranes (MAMs). These contacts occupy about 5–20% of the mitochondrial surface and play a crucial role in the exchange of calcium, lipids, and signaling molecules [24]. Through MAMs, Ca²⁺ is transferred from the ER to mitochondria via protein complexes like IP₃R-GRP75-VDAC. Calcium entering the mitochondria activates dehydrogenases of the Krebs cycle and enhances ATP synthesis. However, excessive Ca²⁺ flux opens the mPTP and induces necrosis [25]. Furthermore, MAMs participate in lipid metabolism: they synthesize phosphatidylserine and its conversion to phosphatidylethanolamine, and coordinate mitochondrial biogenesis. MAM dysfunction is associated with insulin resistance and the development of MASLD [26]. The protein MFN2, which controls mitochondrial fusion, also participates in MAM formation. Its deficiency in mice is accompanied by impaired lipid metabolism and the development of steatohepatitis [27]. Thus, the functional integrity of MAMs is an important factor in maintaining the metabolic equilibrium of the liver. 6. Role of Mitochondria in Liver Metabolism. Hepatocyte mitochondria support key metabolic pathways: β-oxidation of fatty acids in the matrix is the main source of ATP and a key process in preventing hepatic steatosis; the tricarboxylic acid (TCA) cycle integrates the catabolism of carbohydrates, lipids, and amino acids; ketogenesis—synthesis of ketone bodies (via HMG-CoA lyase, HMGCS2) during fasting; the urea cycle—detoxification of ammonia via mitochondrial enzymes CPS1, OTC, and NAGS; biosynthesis of bile acids through mitochondrial CYP27A1 and regulation of cholesterol metabolism [28, 29]. Disruption of any of these pathways leads to lipid accumulation, hyperammonemia, and cytotoxicity. In MASLD, suppression of βoxidation and OXPHOS, reduced CPS1 activity, and hypoexpression of PGC-1α—the main coactivator of mitochondrial biogenesis—are observed [30]. 7. Mitochondrial Dysfunction in Liver Diseases. Mitochondrial damage is a key mechanism in the progression of chronic liver diseases, regardless of etiology. MASLD: Excess free fatty acids → overload of the respiratory chain → increased ROS and lipotoxicity. Mitochondrial fragmentation, MFN2 deficiency, and suppressed mitophagy are noted [31]. Alcoholic Liver Disease: Acetaldehyde and CYP2E1 induce ROS and lipid peroxidation; mitochondria lose cristae and membrane potential [32]. Drug-Induced Injury (Acetaminophen): Reactive metabolites like NAPQI are formed → mitochondrial nitrosative stress and mPTP opening [33]. Ischemia-Reperfusion: A burst of ROS and Ca²⁺ overload upon restored blood flow activate mPTP and apoptosis [34]. All these conditions share a common pathogenetic node—the disruption of mitochondrial dynamics and redox homeostasis. 8. Perspectives for Therapeutic Correction. Current research is focused on finding drugs that can stabilize mitochondrial function. Promising approaches include: activators of PGC-1α and SIRT3 (resveratrol, nicotinamide riboside) to enhance biogenesis and antioxidant defense; SOD mimetics and glutathione donors (GABA, N-acetylcysteine); mPTP inhibitors (cyclosporine A, NIM811); agonists of PPARα and AMPK to normalize lipid metabolism [35–37]. These approaches form the basis of mitochondria-targeted therapy for liver diseases, aimed not only at alleviating symptoms but also at restoring the energy potential of hepatocytes. 9. Ultrastructural Changes of Mitochondria in Liver Pathology. Electron microscopy studies show that in injuries of various etiologies, hepatocyte mitochondria undergo profound structural rearrangements. In early stages, moderate matrix swelling, reduction in the number of SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 11 NOVEMBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 59 cristae, and condensation of the inner membrane are observed; in later stages—fragmentation, vacuolization, and rupture of the outer membrane occur [38]. In steatohepatitis (MASLD), mitochondria become rounded, with disorganized cristae and lipid inclusions. The phenomenon of "megamitochondria"—giant organelles with condensed matrix and disrupted membranes—is often identified, reflecting an adaptive response to excessive β-oxidation [39]. In alcoholic damage, mitochondria swell, their matrix becomes electron-lucent, and fragmentation and loss of cristae are noted. The activity of NADH dehydrogenase (Complex I) sharply decreases, while cytochrome P450 2E1 remains hyperactive, enhancing ROS generation [40]. In drug-induced hepatitis (e.g., acetaminophen-induced), opening of the mitochondrial permeability transition pore (mPTP), uncoupling of oxidative phosphorylation, collapse of the membrane potential, and hepatocyte necrosis are observed [41]. Ultrastructural signs of mitochondrial stress are one of the early morphological markers of liver damage, preceding biochemical changes. Their visualization using transmission electron microscopy and digital morphometry allows for a quantitative assessment of the degree of organelle damage and therapy efficacy [42]. 10. Mitochondrial Signaling and Interorgan Interactions. Mitochondria not only produce energy but also serve as universal signaling hubs. They regulate apoptosis, inflammatory responses, and adaptation to stress. The release of mitochondrial DNA (mtDNA) into the cytosol activates innate immune receptors (TLR9, cGAS–STING), promoting cytokine production and the development of systemic inflammation [43]. In the context of the liver, mitochondrial DNA and outer membrane proteins (VDAC, TOMM20) act as damage-associated molecular patterns (DAMPs), causing macrophage infiltration and Kupffer cell activation [44]. This process underlies the transition from steatosis to steatohepatitis and fibrosis. Furthermore, mitochondria participate in signaling between organs—the so-called mitochondrial endocrine axis. It has been shown that mitochondrial metabolites (succinate, α-ketoglutarate, acetate) can influence gene expression in other tissues, including adipose and muscle tissue, through epigenetic mechanisms [45]. This makes mitochondria a systemic regulator of homeostasis and explains the multi-organ manifestations of liver diseases. 11. Mitochondrial Biogenesis and Regeneration. The mitochondrial pool is maintained through biogenesis processes controlled by nuclear-cytoplasmic factors. The coactivator PGC-1α (peroxisome proliferator-activated receptor γ coactivator-1α) plays a central role, activating the transcriptional factors NRF1/2, which induce the expression of the mitochondrial transcription factor TFAM. The latter regulates the replication and transcription of mtDNA [46]. Upon liver injury, PGC-1α activity decreases, leading to a deficit of new mitochondria and exacerbating the energy deficit. Experiments have shown that activation of the AMPK–SIRT1–PGC-1α pathway (by metformin, resveratrol, physical exercise) stimulates biogenesis and increases hepatocyte resistance to stress [47]. Biogenesis is closely coordinated with mitophagy: the removal of defective mitochondria is accompanied by the synthesis of new ones, ensuring constant organelle renewal—the so-called mitochondrial quality cycle. This process is particularly important for tissues with high metabolic rates, such as the liver [48]. 12. Modern Directions in Morphofunctional Research. Modern methods for studying mitochondria include electron microscopy, fluorescence imaging, immunocytochemistry, and molecular approaches (RT-PCR, Western blot, qPCR of mtDNA/nDNA). Digital morphometry and software segmentation (ImageJ, Imaris) enable quantitative assessment of area, cristae density, the ratio of healthy to damaged mitochondria, the degree of collagen deposition, and the staining SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 11 NOVEMBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 60 intensity of markers like PINK1, Parkin, MFN2, and DRP1 [49]. These methods are particularly important in experimental liver morphology, where the correlation between structural and biochemical parameters (ATP, NADH, Ca²⁺, ROS) allows for building pathogenetic models and predicting therapy efficacy. Conclusions 1. Hepatocyte mitochondria constitute a dynamic system that ensures the energy and metabolic stability of the liver. 2. Balanced fusion and fission processes, regulated by MFN1/2, OPA1, and DRP1, maintain the morphological integrity of the mitochondrial pool. 3. Impairment of mitophagy, particularly the PINK1/Parkin pathway, leads to the accumulation of damaged organelles and the activation of inflammatory processes. 4. MAMs provide a critical link between the endoplasmic reticulum and mitochondria, controlling calcium and lipid exchange. 5. Oxidative stress is a key pathogenetic mechanism of mitochondrial damage in MASLD, alcoholic, and drug-induced liver injury. 6. Current experimental data confirm that the activation of biogenesis (via PGC-1α, SIRT3) and mitophagy promotes the restoration of energy potential and reduces cytotoxicity. 7. Comprehensive study of the morphofunctional and molecular aspects of mitochondria opens new avenues for the diagnosis and mitochondria-targeted therapy of liver diseases. REFERENCES 1. Benda C. Über die Mitochondrien. Verh. Physiol. Ges. 1898. 2. 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