Origin and Function of Mitochondria

Mitochondria, found in almost all eukaryotic cells, play an essential role in cellular metabolism (Megías et al., 2023). These double-membrane structures can grow, divide, fuse, and alter their morphology according to the cell’s needs. Their origin dates back to an endosymbiotic association between ancestral respiratory alpha-proteobacteria and archaeal lineages, which gave rise to eukaryotic cells. Although their principal function is energy production, Megías et al. (2023) note that they also participate in various cellular processes that contribute to the organism’s proper functioning.

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¿Qué son las Mitocondrias?

Mitochondria are essential organelles in eukaryotic cells, as they play a key role in producing the energy required for cellular function (Montagud Rubio, 2020). Their elongated shape and double membrane with numerous internal folds allow specialized proteins to facilitate the generation of adenosine triphosphate (ATP), the cell’s main energy currency. The number of mitochondria in a cell varies according to its energy demands (Montagud Rubio, 2020). In line with Montagud Rubio (2020), tissues with high metabolic demand, such as the liver, typically contain more of these organelles because hepatocytes require a constant energy supply for essential enzymatic processes.

Origen Mitocondrial

In 1980, Lynn Margulis revitalized an old theory about the origin of this organelle and reformulated it as the endosymbiotic hypothesis (Montagud Rubio, 2020). According to this hypothesis, about 1.5 billion years ago, a prokaryotic cell capable of generating energy from organic nutrients using molecular oxygen as an oxidant fused with — or was engulfed by — another prokaryotic cell, or possibly an early eukaryotic cell, without being digested. Montagud Rubio (2020) points out that this phenomenon is supported by observations showing that some bacteria can engulf others without compromising their own viability.

The engulfed cell then established a symbiotic relationship with the host, providing ATP in exchange for a stable, nutrient-rich environment (Montagud Rubio, 2020). This mutual benefit led to the integration of the engulfed cell as an indispensable component of the host cell, giving rise to the mitochondrion. Montagud Rubio (2020) further strengthens the hypothesis by highlighting morphological similarities between free-living bacteria and mitochondria: both are elongated, possess analogous membranes, and—most importantly—contain circular DNA. Moreover, mitochondrial DNA (mtDNA) is notably different from nuclear DNA, suggesting the existence of two distinct genetic entities.

Structural and Functional Characteristics

Mitochondria are small structures, measuring between 0.5 and 1 μm in diameter and up to 8 μm in length (Montagud Rubio, 2020). Their semi-spherical to elongated shape varies according to cellular demands. The number of mitochondria in a cell is determined by its energy requirements, so cells with higher energy consumption contain more of these organelles. Collectively, the cell’s mitochondrial population is called the “chondriome.” Each mitochondrion is bounded by two membranes with distinct enzymatic activities, dividing its internal architecture into three compartments: the cytosolic side (intermembrane space), the intermembrane space, and the mitochondrial matrix, where key energy-producing processes occur (Montagud Rubio, 2020).

Outer Membrane

The outer mitochondrial membrane is a lipid bilayer that permits the passage of ions, metabolites, and various polypeptides (Montagud Rubio, 2020). Its structure contains specialized proteins called porins, which form a voltage-dependent anion channel. These channels facilitate the transit of large molecules up to 5,000 daltons in weight and approximately 20 ångströms in diameter. Unlike other mitochondrial structures, the outer membrane has a limited role in enzymatic or transport processes. Nevertheless, Montagud Rubio (2020) reports that its composition is 60% – 70% protein, contributing to its functionality within the cell.

Inner Membrane

The inner mitochondrial membrane is composed of approximately 80% protein and is distinguished by its high selectivity, since it contains no pores (Montagud Rubio, 2020). Its structure houses numerous enzymatic complexes and transmembrane transport systems, which play a fundamental role in translocating molecules from one compartment to another within the cell.

Mitochondrial Cristae

The inner membrane of the mitochondrion forms multiple inward folds known as mitochondrial cristae (Megías et al., 2023). These structures can take three main morphological forms: discoidal, tubular and flattened. Their protein composition differs from the rest of the inner membrane, suggesting functional specialization within the mitochondrion (Megías et al., 2023). The number of cristae correlates with cellular activity, as they significantly increase the surface available for the binding of proteins essential to various metabolic processes (Montagud Rubio, 2020). Moreover, according to Montagud Rubio (2020), these cristae connect to the inner membrane at specific points that facilitate metabolite transport between mitochondrial compartments.

Among their primary functions, mitochondrial cristae are key players in oxidative metabolism, particularly in the electron transport chain and oxidative phosphorylation (Montagud Rubio, 2020). The respiratory chain includes four fixed enzymatic complexes and two mobile electron carriers. According to Montagud Rubio (2020), the proton channel and ATP synthase participate in adenosine triphosphate (ATP) synthesis, while various transport proteins regulate the passage of molecules such as fatty acids, pyruvic acid, adenosine diphosphate (ADP), ATP, oxygen, and water.

Intermembrane Space

The intermembrane space lies between the inner and outer membranes and contains a fluid similar to cytoplasm (Montagud Rubio, 2020). Its high proton concentration results from proton pumping by the respiratory-chain enzymatic complexes, contributing to the electrochemical gradient necessary for ATP synthesis. This space houses enzymes involved in high-energy phosphate transfer from ATP, notably adenylate kinase and creatine kinase. Additionally, according to Montagud Rubio (2020), carnitine is present—an essential molecule for transporting fatty acids from the cytosol into the mitochondrion for oxidation and energy production.

Mitochondrial Matrix

The mitochondrial matrix, also called the mitosol, contains fewer molecules than the cytosol (Montagud Rubio, 2020). However, it houses ions, metabolites in various stages of oxidation, circular DNA similar to bacterial DNA, and mitochondrial ribosomes (mitoribosomes), which synthesize certain mitochondrial proteins from mitochondrial RNA. This matrix shares features with organelles in free-living prokaryotes, which lack a nucleus. Furthermore, according to Montagud Rubio (2020), essential metabolic processes such as the Krebs cycle and fatty-acid β-oxidation—crucial for cellular energy production—occur within this compartment.

Mitogenome or mtDNA

Mitochondria possess their own DNA, known as the mitogenome or mtDNA, making them the only organelle with genetic material (Rothschuh, 2025). This circular DNA is smaller and works in coordination with nuclear DNA to regulate various cellular functions. Unlike nuclear DNA, the mitogenome is inherited exclusively maternally and does not undergo genetic recombination. Due to its proximity to oxidative metabolism and lack of protective histones, mtDNA is more vulnerable to mutations, which can lead to diseases such as Parkinson’s. Its study has been key to understanding cellular evolution, supporting the endosymbiotic theory. Rothschuh (2025) notes that, according to this hypothesis, a prokaryotic cell engulfed an aerobic bacterium, giving rise to the mitochondrion and establishing a symbiotic relationship essential for the evolution of eukaryotic cells.

Fusion and Fission

Mitochondria can continuously divide and fuse within cells, allowing mitochondrial DNA to form an interconnected network rather than exist as individual organelles (Montagud Rubio, 2020). This process facilitates the distribution of synthesized products, correction of local defects and exchange of genetic material. According to Montagud Rubio (2020), when two cells with distinct mitochondria fuse, the resulting mitochondrial network becomes homogeneous in approximately eight hours.

Due to ongoing mitochondrial fusion and fission, determining the exact number of these organelles in a cell is complex (Montagud Rubio, 2020). However, tissues with high energy demands tend to have more mitochondria because of increased fission events. Mitochondrial division is regulated by dynamin - like proteins responsible for vesicle formation. Moreover, according to Montagud Rubio (2020), interaction with the endoplasmic reticulum plays a key role in this process, as its membranes wrap around the mitochondrion, creating a constriction that ultimately leads to its division.

Functions

The primary function of mitochondria is to produce ATP, the essential fuel for cellular processes; they also participate in fatty-acid metabolism via β-oxidation and serve as a calcium reservoir (Montagud Rubio, 2020). Furthermore, according to Montagud Rubio (2020), recent research has linked mitochondria to apoptosis, cancer, aging and various degenerative disorders such as Parkinson’s disease, diabetes and Alzheimer’s disease.

ATP Synthesis

In mitochondria, the majority of ATP in non-photosynthetic eukaryotic cells is generated. This process begins with acetyl-coenzyme A metabolism through the citric-acid cycle, producing CO₂ and NADH (Montagud Rubio, 2020; Megías et al., 2023). NADH then transfers electrons to a chain of carriers located in the cristae membranes, and these electrons move until they reach an oxygen molecule, forming water (Montagud Rubio, 2020; Megías et al., 2023). According to Montagud Rubio (2020), this electron flow is coupled to proton transport from the matrix to the intermembrane space, creating an electrochemical gradient crucial for ATP synthesis.

Through ATP synthase action, this proton gradient drives the attachment of a phosphate to ADP, using oxygen as the final electron acceptor in the process known as oxidative phosphorylation (Montagud Rubio, 2020). The electron-transport chain, or respiratory chain, comprises about 40 proteins, of which 15 directly participate in electron transfer, grouped into three protein complexes: NADH dehydrogenase, cytochrome b-c₁ and cytochrome oxidase (Megías et al., 2023). Each complex contains chemical groups that facilitate proton passage, generating a gradient with a significantly higher proton concentration in the intermembrane space than in the matrix. In addition to driving ATP synthesis, this gradient also promotes the transport of other charged molecules (Megías et al., 2023). For example, pyruvate, ADP and inorganic phosphate enter the matrix via proton-coupled symport, while ATP is expelled to the cytosol by an ADP/ATP antiport mechanism.

Lipid Metabolism

Mitochondrial activity significantly contributes to lipid synthesis in cells, as lysophosphatidic acid — a precursor of triacylglycerols — is generated in this organelle (Montagud Rubio, 2020). Additionally, according to Montagud Rubio (2020), phosphatidic acid and phosphatidylglycerol —essential for cardiolipin and phosphatidylethanolamine formation—are produced, crucial for cellular-membrane structure and function.

Protein Import

Despite having relatively few genes compared to the diversity of proteins they contain, mitochondria exhibit remarkable proteomic complexity (Megías et al., 2023). For instance, a yeast mitochondrion hosts around 1,000 different proteins, while in humans the number can reach 1,500. Only a small fraction of these proteins is synthesized within the organelle; most are produced in the cytosol and then imported into mitochondria. Megías et al. (2023) explain that during import, proteins are directed to specific compartments by signal sequences that act like postal addresses, guiding them to their correct mitochondrial destination.

Mitochondrial Renewal

The mitochondrial population within a cell is constantly renewed by the removal and synthesis of new organelles (Megías et al., 2023). New mitochondria arise only from preexisting ones, while those that have completed their function are degraded by macroautophagy, which clears large amounts of cytoplasmic content. According to Megías et al. (2023), this balance between synthesis and degradation ensures the functionality and dynamics of the mitochondrial network.

Mitochondria in Circulation

In early 2020, functional free mitochondria were reported in the mammalian circulatory system (Olvera Sánchez et al., 2023). In cell cultures, both free mtDNA and intact, operational mitochondria were observed; likewise, studies on human and bovine serum found similar results, with bovine-serum mitochondria remaining detectable and functional even after treatment at 56 °C for 30 minutes. Moreover, Olvera Sánchez et al. (2023) documented that platelet-derived mitochondria have chemokine receptors, suggesting their involvement in immune processes via reprogramming of cell differentiation.

It has also been proposed that extracellular mitochondria could help restore cellular homeostasis, accumulating in energy-deficient areas or responding to immunological stimuli in certain tissues (Olvera Sánchez et al., 2023). However, despite approximately 1.4 × 10⁶ mitochondria per milliliter of blood being identified via fluorescent markers like MitoTracker, the electron-transport chain did not exhibit full activity, indicating the need to further investigate the role of free mitochondria in blood. Finally, according to Olvera Sánchez et al. (2023), the presence of mitochondria in cerebrospinal fluid may serve as a biomarker for certain neurological diseases, so caution is advised when using fetal bovine serum in experiments, as these mitochondria could affect results.

Intercellular Mitochondrial Transfer

Certain cells — especially mesenchymal/stromal stem cells (MSCs) — can transfer mitochondria to damaged cells, as can other cell lines from bone marrow, adipose tissue, dental pulp and Wharton’s jelly (Olvera Sánchez et al., 2023). According to Olvera Sánchez et al. (2023), this mechanism—perhaps a remnant of the ancient endosymbiotic relationship — occurs in three stages: first, highly specific molecular signals from damaged cells or microenvironmental factors initiate the process; second, an intercellular structure forms to facilitate transfer; and finally, transferred mitochondria must perform or enhance bioenergetic functions in recipient cells.

The signals inducing this process vary with tissue type and physiological conditions, involving factors such as ischemia (which exposes phosphatidylserine on the cell surface), matrix metalloproteinase 1 (MMP-1), the intermediate filament protein nestin, proinflammatory cytokines and inflammatory stress, as well as chemotherapy-induced conditions and a proinflammatory microenvironment (Olvera Sánchez et al., 2023). Additionally, Olvera Sánchez et al. (2023) describe how NOX2-derived superoxide in severely dysfunctional cells stimulates reactive-oxygen-species generation in the bone-marrow stroma, increasing mitochondrial donation to affected cells in acute myeloid leukemia.

Furthermore, CD38 — a transmembrane‐signaling and adhesion ectoenzyme — modulates intracellular Ca²⁺ levels to generate cyclic ADP-ribose, which is also associated with this mechanism (Olvera Sánchez et al., 2023). Olvera Sánchez et al. (2023) note that together these factors vary by the state of damaged cells and the surrounding microenvironment, determining the efficiency of intercellular mitochondrial transfer.

Mitochondrial Tunneling Bridges

Various mechanisms have been reported for intercellular mitochondrial transfer, including gap junctions, extracellular vesicles, free extracellular mitochondria, cytoplasmic fusion and tunneling nanotubes (TNTs) (Olvera Sánchez et al., 2023). TNTs, which are nanotubes capable of bidirectional transport of proteins, lipid droplets, ions, RNA (including microRNA), organelles, viruses and cytosol. Two types of TNTs have been described: thick ones, which preferentially transfer mitochondria and form long, large-diameter channels (600–700 nm) containing microfilaments, microtubules and F-actin; and thin ones composed solely of F-actin. According to Olvera Sánchez et al. (2023), these TNTs act as scaffolds for proteins such as Miro1, Miro2, TRAK1, TRAK2, Myo19 and Kif5c, which drive mitochondrial movement between cells.

Electron micrographs have been useful in illustrating TNT formation in cells (Olvera Sánchez et al., 2023). In certain biological systems—especially under stress, ischemic conditions or in tumors—mitochondrial transit from healthy to compromised cells has been observed. Olvera Sánchez et al. (2023) state that although information on intercellular mitochondrial transport has unlocked novel mitochondrial functions inside and outside cells, it remains unclear whether the donation of healthy mitochondria is entirely beneficial or may, in some cases, have adverse effects.

Mitochondrial Medicine

Mitochondrial transfer has been applied in animal experiments and in tissues affected by various diseases, a procedure known as “mitochondrial medicine” or “mitocuring” (Olvera Sánchez et al., 2023). In some countries, these strategies are approved even for addressing oocyte fertilization issues in reproductive biology. Studies indicate that mitochondria from healthy cells transferred to cells under unfavorable conditions—such as in cancer or oxidative stress—can modify the bioenergetic state of tumor tissue. However, according to Olvera Sánchez et al. (2023), some tumor cells that capture healthy mitochondria may enhance their growth and resistance to anticancer treatments, generating chemoresistance; therefore, transfer must be evaluated case by case depending on the pathology.

Moreover, co-culture systems have shown that cells can incorporate isolated mitochondria as a recovery method, leading to new strategies for mitochondrial isolation in therapy (Olvera Sánchez et al., 2023). Experimentally, this technique has succeeded in animal models of diabetes or ischemic injury, improving cardiac protection. Subsequently, after its application in animal models, mitochondrial transfer has begun to be used in treating some human diseases. For example, according to Olvera Sánchez et al. (2023), in an autotransplantation performed on five pediatric patients with cardiac ischemia, four showed improved ventricular function and were weaned off extracorporeal membrane oxygenation (ECMO).

In another study, ten pediatric patients undergoing intracardiac mitochondrial transplantation experienced an 80% recovery rate compared to 29% in the control group (Olvera Sánchez et al., 2023). With these results, Olvera Sánchez et al. (2023) suggest that this therapy may soon be implemented to improve outcomes in hard-to-treat diseases, although more knowledge is needed about these techniques where mitochondria play a previously underappreciated role.

Mitochondria: Cellular Energy and Health

Given their central role in cellular metabolism and energy production, mitochondria are crucial for health and disease (Álvarez, 2023). Mitochondrial dysfunction is implicated in metabolic, neurodegenerative, cardiovascular disorders and cancer. According to Álvarez (2023), in hereditary mitochondrial diseases, mutations in mtDNA or nuclear genes affecting mitochondrial function lead to multi-system disorders.

Various factors increase the mitochondrial genome’s mutation rate: its constant replication raises the chance of errors, and as the respiratory organelle, its DNA is continually exposed to toxic oxygen derivatives known as reactive oxygen species (ROS), which can damage its structure (Torrentí Salom, 2018). Indeed, Torrentí Salom (2018) describes about 150 mitochondrial-genome mutations associated with diseases that impair energy production, since this genome encodes only 13 essential proteins, the rest having been transferred to the nucleus during endosymbiotic evolution.

High-energy-demand tissues—such as muscles, brain, heart, liver and kidneys—are most vulnerable (Torrentí Salom, 2018). Examples include Leber’s hereditary optic neuropathy (LHON), causing bilateral central vision loss from optic-nerve atrophy; myoclonic epilepsy with ragged-red fibers (MERRF), characterized by epilepsy, seizures, myopathy and sometimes dementia, deafness, optic atrophy, respiratory failure or cardiomyopathy; and maternally inherited deafness-diabetes syndrome, as its name implies.

Mitochondria and Aging

Aging has been linked to progressive mitochondrial deterioration and accumulation of oxidative damage in these organelles (Álvarez, 2023). The mitochondrial senescence theory proposes that with advancing age, mitochondria become less efficient at energy production while generating more free radicals. According to Álvarez (2023), this imbalance between energy generation and oxidative stress may contribute to cellular aging and age-related diseases.

Mitochondria: Key to Cellular Health

Mitochondrial biology research continues to evolve, driven by studies exploring mitochondrial function and biogenesis (Álvarez, 2023). Active investigations focus on the metabolic pathways they participate in and the regulatory mechanisms governing their biogenesis and dynamics. Potential therapeutic strategies aimed at improving mitochondrial function in related diseases have been identified. In summary, mitochondria are essential for energy production, cellular metabolism and oxidative-stress regulation; their unique structure and functional diversity make them fundamental to cellular health. Furthermore, according to Álvarez (2023), ongoing study of these organelles and their roles in various pathologies offers new perspectives on cellular mechanisms and innovative therapeutic approaches.

References

1. Álvarez, J. (2023, enero 4). Mitocondrias: Definición y Funciones. Mentes Abiertas Psicología S.L. https://www.mentesabiertaspsicologia.com/blog-psicologia/mitocondrias-definicion-y-funciones

2. Megías, M., Molist, P., & Pombal, M. Á. (2023). Mitocondrias. Atlas de Histología Vegetal y Animal. https://mmegias.webs.uvigo.es/5-celulas/6-mitocondrias.php

3. Montagud Rubio, N. (2020, marzo 6). Mitocondrias: Qué Son, Características y Funciones. Psicología y Mente. https://psicologiaymente.com/salud/mitocondrias

4. Olvera Sánchez, S., Gómez Chang, E., Flores Herrera, O., & Martínez, F. (2023). Las Mitocondrias: Sus Funciones, las Relaciones con Otros Organelos, la Supervivencia Celular y la Medicina Mitocondrial. TIP Revista Especralizada en Ciencias Químico - Biológicas, 26. https://doi.org/10.22201/fesz.23958723e.2023.547

5. Rothschuh, U. (2025). Mitocondrias: Función y Estructura. ecologiaverde.com. https://www.ecologiaverde.com/mitocondrias-funcion-y-estructura-3693.html

6. Torrentí Salom, F. (2018, mayo 23). Una Célula Dentro de tu Célula: La Mitocondria. Genotipia. https://genotipia.com/mitocondria/