Mitochondria in Health and Disease: History
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Contributor:
Sónia A. Pinho
,
Sandra I. Anjo
,
Teresa Cunha-Oliveira

Mitochondrial alterations have been implicated in a wide range of diseases, such as neurodegenerative disorders, metabolic disorders, and cancer. 

  • mitochondria
  • redox homeostasis
  • drug development
  • bioenergetics
  • cell metabolism
  • cellular signaling
  • organelle communication

1. Mitochondria as Dynamic Cellular Information Hubs

Mitochondria are renowned for their role as the powerhouses of the cell, responsible for producing most of the cellular energy in the form of adenosine triphosphate (ATP) through the process of oxidative phosphorylation (OXPHOS) [1]. However, mitochondria are involved in many processes beyond energy production. Mitochondria play a critical role in determining cell function and fate, playing roles in different cell processes, including, but not limited to, cell division, differentiation, calcium (Ca2+) signaling, autophagy, and apoptosis. Therefore, while their function as the cell’s powerhouse is undoubtedly significant, it is only one of many crucial roles that mitochondria play in maintaining cellular homeostasis [1][2][3]. Recognizing the diverse and multifaceted roles of mitochondria in cellular processes has led to the proposal of a new conceptualization of these organelles as central hubs for intracellular signal processing and integration. It is now understood that mitochondria are sophisticated information processing centers that are capable of sensing and responding to a wide range of signals from both within and outside the cell. This ability to integrate and respond to multiple signals makes mitochondria critical regulators of cellular function and highlights their importance in maintaining cellular homeostasis [4][5][6]. This new paradigm recognizes the complex interplay between mitochondrial function and various cellular processes, including metabolism, gene expression, and cellular signaling. Mitochondria play a critical role in regulating cellular behavior and maintaining cellular homeostasis by serving as hubs for integrating these signals. The updated conceptualization of mitochondria as an information processing system provides a more nuanced and comprehensive understanding of the functions of these organelles, emphasizing their central role in the complex web of cellular interactions that regulate cellular physiology and behavior [4].
Mitochondria are distinct cellular organelles with their own DNA (mtDNA) and a double-membrane system consisting of the mitochondrial outer (MOM) and inner membrane (MIM). Mitochondria also engage in extensive communication with other organelles. For example, they cooperate with peroxisomes in the catabolism of fatty acids through β-oxidation, share fission machinery components, and participate in redox signaling relationships [7]. Additionally, mitochondria interact with the endoplasmic reticulum (ER) in the regulation of Ca2+ homeostasis, lipid metabolism, and mitochondrial fission and autophagy [8], as well as with lysosomes in the regulation of mitophagy and fission [9]. Furthermore, mitochondria communicate with the Golgi apparatus in regulating mitochondrial dynamics [10] and with the nucleus for regulating cellular metabolism [10][11][12]. This communication underscores the social nature of mitochondria and their critical role in coordinating cellular processes. This organelle crosstalk is a key component of mitochondrial signaling in physiology and pathology.
Mitochondria are highly dynamic organelles moving in the cell by taking advantage of the microtubule network and dynamically changing their morphology by fission and fusion processes through specialized protein machinery that includes cytosolic dynamin-related protein 1 (DRP1) for fission and mitofusin (MFN1/2) and optic atrophy 1 (OPA1) for fusion at the MOM and MIM, respectively [13]. Cristae are also very dynamic structures whose shape and bioenergetic capacity change with physiological conditions, such as substrate availability, glucose, or oxygen (O2) deprivation [14][15]. The remodeling of cristae structure and OXPHOS function has been associated with alterations in cellular metabolism [14][16].
Recent findings using a powerful new tool called MitCOM have shown that the organization and interaction of mitochondrial proteins is more intricate than previously assumed [17]. MitCOM is based on high-resolution complexome profiling, which allows for the quantification of mitochondrial protein assemblies in the yeast mitochondrial proteome. This approach has provided new insight into mitochondrial protein machinery’s dynamics and molecular composition, revealing a more complex picture of mitochondrial function and organization [17]. The mitochondrial respiratory chain (MRC), also known as the electron transport chain (ETC), consists of enzymes that form supramolecular structures called supercomplexes (SCs). This evidence contradicts the traditional fluid model of dispersed enzymes in the MIM and in cristae membranes [18][19]. Complexes I, III, and IV can assemble into one SC known as the respirasome [18][20]. Recent evidence has shown the co-existence of two independent MRC structures: the C-MRC, which is bioenergetically more efficient under oxidative metabolic conditions, and the S-MRC, which emerges when metabolic reconfiguration favors glycolysis. These structures have been described in human skin fibroblasts and the HEK 293T and osteosarcoma 143-B cell lines, as well as postmitotic tissues, such as the brain frontal cortex and skeletal muscle [21]. The two structures are regulated by three isoforms of the mitochondrial respiratory SC assembly—stabilizing factor, COX7A (COX7A1/2), and SC assembly factor 1 (SCAF1, also known as COX7RP and COX7A2L)), as well as by the state of the pyruvate dehydrogenase complex (PDH), which in its active form promotes OXPHOS and the C-MRC structure. When PDH is inactive, representing a metabolic shift to glycolysis, the S-MRC structure is promoted. This important discovery emphasizes the link between metabolic reconfiguration and the MRC architecture, involving SC reorganization in response to environmental signals, such as variations in the metabolic conditions, increased oxidative stress, or the instability of individual complexes [20][21]. Cytochrome c oxidase (COX), also known as complex IV, is composed of 13 different subunits encoded by both nuclear and mitochondrial genomes and catalyzes the transfer of electrons from cytochrome c to molecular O2, generating water as a byproduct. COX activity is fine-tuned in response to various physiological conditions, and this regulation may include the incorporation of different COX subunit isoforms produced through alternative splicing of nuclear-encoded subunit isoforms and/or post-translational modifications, including reversible phosphorylation. It can also occur through the binding of nucleotides, hormones, or proteins/enzymes and by the formation of SC with other complexes involved in OXPHOS [22][23]. Thus, mitochondrial dynamic activity is correlated with energy demand and nutrient supply, responding to bioenergetic adaptation.
Mitochondria have two mechanisms for controlling metabolism, homeostasis and adaptation, which primarily differ in how metabolic sensing and downstream effects are coupled. Homeostasis refers to the maintenance of a relatively stable internal environment, while adaptation refers to the ability to adjust to environmental changes. Mitochondria, as biosynthetic organelles with metabolically plastic and unique stress response processes, require both homeostasis and adaptation mechanisms to maintain optimal function. Two distinct circuits of metabolic control, feedforward and feedback control, are used to achieve metabolic homeostasis or metabolic adaptation in response to perturbations [5]. Feedback control circuits exert a direct effect on the sensed metabolic parameter retroactively to counteract perturbations via a negative feedback mechanism, while feedforward control mechanisms rewire the metabolic network to ensure adequate metabolic output in the presence of perturbation [5]. In some scenarios, these two circuits act simultaneously, engaging a downstream effector that both maintains homeostatic control and promotes an adaptive response [5].
Maintaining a proper balance of several mitochondrial processes, including biogenesis, dynamics, proteostasis, mitophagy, Ca2+ homeostasis, and redox signaling, is essential for the maintenance of healthy mitochondria [2][3][24]. These processes work together to create mitochondrial quality control mechanisms, ensuring that dysfunctional mitochondria are eliminated and healthy ones are maintained. However, when these balances are disrupted, mitochondria can become dysfunctional, producing an excess of reactive redox species (RRS) that surpass the capacity of the cellular antioxidant system to detoxify them, leading to oxidative stress [24].
Cellular metabolism relies on a highly interconnected and well-coordinated network of chemical reactions, involving constant intra- and extracellular communication among cell organelles. These reactions organize into several metabolic pathways, such as glycolysis, citric acid cycle (also known as tricarboxylic acid) (TCA), pentose phosphate pathway (PPP), OXPHOS, or fatty acid β-oxidation. Metabolites act as important intermediate molecules and substrates for these biological processes, but some metabolites also function as signaling molecules that can influence the activity of regulatory proteins, nutrient sensing, cell survival and differentiation, and embryonic development, being key regulators of cell phenotype and behavior [24][25]. Mitochondrial metabolites such as acetyl-coenzyme A (ACCoA) can act as second messengers, inducing post-translational modifications that modulate the activity of metabolic enzymes [25][26]. The balance between catabolic and anabolic pathways is crucial to maintaining metabolite levels and ensuring an adequate energy supply. Therefore, cells constantly adapt to different metabolic needs and conditions of cellular stress to maintain normal cellular physiology, relying on mitochondrial plasticity, which plays a crucial role in cellular and mitochondrial homeostasis [25].

2. Mitochondrial Stress

The term “mitochondrial stress” refers to the state of the mitochondria when they are exposed to various stressors that can disrupt their normal functions, such as oxidative stress, nutrient deprivation, mitochondrial DNA damage, and other factors [26][27]. Mitochondrial stress can trigger various cellular responses, including changes in mitochondrial morphology, altered mitochondrial function, and the induction of mitochondrial quality control mechanisms. These responses are critical for maintaining cellular homeostasis and preventing the accumulation of damaged mitochondria, which can lead to cellular dysfunction and disease [28][29] (Table 1). On the other hand, mitohormesis is a biological response where the induction of a reduced amount of mitochondrial stress leads to an increment in health and viability within a cell, tissue, or organism [30][31], which can lead to persistent adaptations that protect the mitochondria and the cell against subsequent stressors [32]. Mitonuclear communication is crucial for coordinating information exchange between the nuclear and mitochondrial stress responses when triggered by potentially harmful stimuli. Among the signals, the most important for hermetic response in mitochondria are reactive species (such as superoxide (O2.−) or hydrogen peroxide (H2O2)), mitochondrial metabolites, proteotoxic signals, mitochondrial to cytosol stress response, release of cytokines (specifically myokine), insulin/IGF-1 receptors, AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR), sirtuins, and unfolded protein response (UPR) [31][33].
Table 1. Alterations of redox and metabolic homeostasis implicated in several diseases.

Disease

Redox- or Metabolic-Related Alterations

References

Cancer

Defects in mtDNA

[34][35][36]
 

Metabolic shift from OXPHOS to glycolysis

[37]
 

Increased mitochondrial fission

[38][39][40][41][42][43]

Metabolic disorders

(T2D, obesity, NAFLD)

TCA cycle and mitochondrial respiratory chain overload

[44][45][46]
 

Mitochondrial malfunction due to the accumulation of free fatty acids in adipose and peripheral tissues (lipotoxicity)

[44][45][46]
 

Increased oxidative stress

[44][45][46]
 

Insulin resistance

[44][45][46]
 

Dysregulation of Ca2+ homeostasis

[45]
 

Compromised mitochondrial bioenergetics

[47]
 

mtDNA mutations

[48][49]

Neurodegenerative diseases

(AD, PD, HD, ALS)

Impaired mitochondrial biogenesis and mitochondrial dynamics

[50][51][52]
 

Excess ROS production

[53]
 

Decreased intracellular Ca2+ buffering

[53]
 

Decreased respiratory capacity and/or loss of mitochondrial transmembrane potential

[54]
 

Disruption of intracellular trafficking-associated neurotoxicity

[47][55][56][57][58]

mtDNA—mitochondrial DNA; OXPHOS—oxidative phosphorylation; TCA—tricarboxylic acid cycle; ROS—reactive oxygen species; AD—Alzheimer’s disease, PD—Parkinson’s disease; HD—Huntington’s disease; ALS—amyotrophic lateral sclerosis.

3. Mitochondrial Dysfunction

Mitochondrial dysfunction can be triggered by internal (genetics/mutations) or external (drug toxicity) causes and is implicated in several diseases, namely, cancer and metabolic and neurodegenerative disorders, among other pathologies [25][59]. Cellular and mitochondrial alterations depend on the type of disease (Table 1).
In cancer cells, an increase in oxidative stress can derive from mutations on ETC complexes, resulting in increased DNA damage, variations of the number and integrity of mtDNA copies per cell, inadequate repair due to the low repair capacity of mitochondrial DNA, mtDNA mutations, and chromosomal abnormalities and instability [34][35][36]. Cancer cells also suffer mitochondrial dysfunction [37] and often metabolic switch from OXPHOS to glycolysis leading to lactate accumulation, which is now considered an important regulator of cancer growth and an active signaling molecule [38][39][40][41][42][43]. In metabolic disorders, such as type 2 diabetes (T2D), obesity, and NAFLD, the main alterations are associated with cell metabolism [48][49]. An excess of nutrient supply and physical inactivity increase the risk of insulin resistance and T2D, contributing to an increase in mitochondrial H2O2 and general oxidative stress levels due to an overload of TCA and ETC or an increase in inflammatory processes [44][45]. The abnormal changes in circulating fuel levels and in how central and peripheral tissues use energy substrates also result in mitochondrial dysfunction throughout several organ systems [53]. Since mitochondria play a crucial role in cell metabolism, researchers have been developing mitochondria-targeted molecules.
Neurodegenerative diseases also have an important component of mitochondrial dysfunction and loss of redox homeostasis, as described in Table 1 [50][51][52][53][54][55][59]. Thus, mitochondria are important drug targets for neurodegenerative diseases, and some small molecules or peptide sequences targeting mitochondria are being developed for different mitochondrial targets, since several mitochondrial structures/functions are affected in these diseases [60].
In addition, mitochondrial dysfunction impacts not only various pathologies but also the abundance and thermal stability of cellular proteins. This has been demonstrated through multidimensional analysis of pre–post thermal proteome profiling (ppTPP) using isobaric peptide tags in combination with pulsed stable isotope labeling by amino acids in cell culture (pulsed SILAC). This analysis allows for the monitoring of time-sensitive adaptations of mature (pre) and newly synthesized proteins (post) to specific insult-inducing stress, allowing the study of mitoprotein-induced stress responses [61].
Exposure to pharmacological drugs and other chemicals can also induce toxicity involving adverse mitochondrial effects in different cells and tissues depending on the type of drug, which can cause mitochondrial dysfunction through multiple mechanisms. Mitochondrial adverse effects of drugs are a common reason for the withdrawal of many drugs from the market, representing expensive failures [62][63]. Several drugs, such as troglitazone for T2D, cerivastatin for hyperlipidemia and cardiovascular disease prevention, and N-phenethylbiguanide for diabetes, have been withdrawn from the market due to their associated toxicity, including hepatotoxicity and rhabdomyolysis leading to renal failure. Additionally, nefazodone, an antidepressant/anxiety drug, was also withdrawn from the market due to its hepatotoxicity associated with mitochondrial damage [62][64][65]. Notably, all of these drugs have been linked to mitochondrial damage as the underlying mechanism of their toxicity.
In summary, mitochondrial alterations and dysfunction have been implicated in various diseases. Understanding the role and mechanisms of mitochondrial alterations in disease pathogenesis may lead to developing novel therapies that target mitochondrial dysfunction to prevent or treat these diseases.

4. Mitochondrial Function as an Important End-Point in Drug Development

As previously mentioned, mitochondrial toxicity is a severe concern in drug development, but it can be predicted through preclinical studies involving mitochondrial safety screenings [66], which are essential to identify mitochondrial liabilities in the early stages of drug development [67]. Understanding harmful drug–mitochondrial interactions could aid in creating safer treatment plans for individual patients, which is important in precision medicine [62]. However, compounds’ complete range of effects on mitochondrial function cannot be assessed without standardized systematic techniques properly designed and validated to screen and characterize them. This is necessary to determine their safety, therapeutic windows, and potential applications. In fact, even candidate mitochondrial protectants must be screened for potential mitochondrial liabilities to determine their safe concentration windows.

This entry is adapted from the peer-reviewed paper 10.3390/antiox12051072

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