Edited by Saurish Kapoor.
Mitochondria: commonly referred to as “the powerhouse of the cell”. A phrase repeated by biologists and scientists alike for years implicates the major role mitochondria play in our cells. Akeen to the repeated phrase, mitochondria hold within them the secrets to a dance of biochemical complexity that produces energy in the form of adenosine triphosphate (ATP) for the sustenance of every living organism. However, what happens when this majestic machinery is impaired? Together, we shall unravel the depths of mitochondrial dysfunction.
Physiological functions of the mitochondria
To understand the dysfunctional physiology of mitochondria, we should first understand the physiological function of mitochondria. Under physiological conditions, fatty acids, carbohydrates, and other metabolites such as lactate should be successfully transported into mitochondria to be made into ATP. Mitochondria are also the production sites of reactive oxygen species (ROS), which, despite their bad rep in the science community, behave as signalling molecules at physiological levels. Besides, mitochondria also function to regulate genomic expression, cellular activity, and biosynthesis pathways by regulating key metabolites involved, such as acetyl coenzyme A as well as activating or deactivating certain enzymes (Osellame et al., 2012).
Figure 1: The physiological roles of mitochondria in the human body. (Mao et al., 2020).
Causes of mitochondrial dysfunction
There are many causes of mitochondrial dysfunction: genetic mutations, infections, lack of physical activity, nutrient deficiency, ageing, and many more. Mitochondria, unlike other organelles, contain their own DNA separated from the host cell (Margulis, 1970). Since mitochondrial DNA and nuclear DNA both encode proteins used in the mitochondria, genetic mutations in either of those DNA can cause defective mitochondrial proteins to be made, and subsequently affect mitochondrial function (Rusecka et al., 2018). For example, Barth syndrome is caused by a mutation of the tafazzin gene, which encodes a protein needed for cardiolipin (a component of the inner mitochondrial membrane) remodelling. It is characterised by cardiomyopathy, skeletal myopathy, and neutropenia, as well as a large decrease in fatty acids and pyruvate oxidation in the mitochondria (Clarke et al., 2013). Furthermore, infections by bacteria and viruses can also reduce mitochondrial function through a variety of mechanisms such as destroying the membranes of mitochondria (Kim et al., 2013) and increasing the mitochondrial fission rate (Fields et al., 2016). Besides, bed studies have elucidated the role of sedentary lifestyles on mitochondrial function. Bed rest downregulates metabolic pathways associated with mitochondria biogenesis, and also reduces the expression of a gene that induces mitochondrial biogenesis (Alibegovic et al., 2010). Besides, nutrient deficiency affects mitochondrial function negatively too. Inside our mitochondria, there are many proteins that each require various cofactors to function properly. For example, enzymes require vitamins, calcium, copper, zinc, and other minerals to function optimally. Deficiency in these nutrients reduces the mitochondria’s capacity to do work (Ames et al., 2005). Finally, the natural process of ageing is also observed together with impaired mitochondria, perhaps due to the imbalance in mitochondrial fission and fusion (Jang et al., 2018).
What are the consequences though?
Defective mitochondria have been implicated in pathological inflammation. Under normal conditions, the mitochondria produce small amounts of ROS in the process of generating energy. In these cases, ROS can act as a signalling molecule, and can also be suppressed by antioxidants in the mitochondria (Kienhöfer et al., 2009). Without diving into the molecular mechanisms, mitochondrial dysfunction induces excessive ROS production, which can lead to downstream increases in various inflammatory molecules (López-Armada et al., 2013). As a result of these inflammatory molecules, cellular mechanisms that cause the degradation of cellular components may ensue (Zitvogel et al., 2010).
Dysfunctional mitochondria also exhibit increased permeability in their membranes. This affects the mitochondria's ability to oxidise macromolecules to produce ATP. As a result, the cell's energy depletes and quickly dies. This permeability can also cause the mitochondria to swell and rupture. The bursting of mitochondria triggers a cascade of events, eventually leading to cell death (Slee et al., 2000).
Figure 2: Consequences of mitochondrial dysfunction. (Sreedhar et al., 2020).
Furthermore, mitochondrial dysfunction resulting in inflammation plays a role in many pathologies, especially that of inflammatory nature. In rheumatoid arthritis, it can increase the inflammatory responsiveness of human chondrocytes and synoviocytes to cytokines, promoting mechanisms that may contribute to joint destruction and pain (Vaamonde-García et al., 2012). Besides, the increased inflammation can decrease the efficiency of autophagy, leading to the accumulation of dysfunctional cells and subsequently an even more inflammatory environment (Caramés et al., 2011).
Type 2 diabetes patients usually have decreased mitochondrial content in their skeletal muscles, mitochondrial oxidative enzymes, and overall mitochondrial function. As a result, patients are characterised by poor fats and carbohydrate oxidation capacity. Hence, cells rely more on glycolysis and the production of lactate to produce ATP (Abdul-Ghani & DeFronzo, 2008). Reduced fat oxidation capacity also causes the accumulation of lipids in the skeletal muscle, which has been proposed to be the igniting spark for the development of insulin resistance (a hallmark of type 2 diabetes) (Bergman & Goodpaster, 2020). Type 2 diabetes patients may also have mitochondria that are unable to oxidise lactate properly. Contrary to popular belief, lactate is not only produced during vigorous exercise, but is produced constantly, and could even be the fuel preferred by most cells (Brooks, 2020). The lactate produced can usually be oxidised by mitochondria-rich cells as a source of energy. However, a dysfunctional mitochondrial lactate oxidation capacity can cause lactate buildup in the cytoplasm. Hyperlactatemia, the presence of abnormally high concentrations of lactate, decreases the expression of a gene GLUT4 that codes for a protein that imports glucose in skeletal muscles. This then decreases glucose uptake and oxidation (Anna Maria Lombardi et al., 1999). In any case, lactate can inhibit lipolysis (the process of breaking down triglycerides into free fatty acids) in adipocytes (Liu et al., 2009). Not only that, when beta cells in the pancreas accumulate mitochondrial damage, they become less able to produce ATP, which decreases their ability to secrete insulin too.
Moreover, our heart is the most oxidative tissue in the body, producing most of its ATP from aerobic glycolysis, and β–oxidation of fatty acids (Zhang et al., 2010). Decreased mitochondrial function has been observed in cardiomyocytes in cases of cardiac hypertrophy and heart failure (Tran & Wang, 2019). Mitochondrial DNA deletion is also more abundant in cardiomyocytes of patients with coronary artery disease (Corral-Debrinski et al., 1992). Defective autophagy caused by excessive inflammation may also lead to myocarditis. Aside from that, atherosclerosis is also correlated with mitochondrial dysfunction, mitochondrial DNA mutations, and mitochondrial damage. Damage caused by excessive ROS production can also lead to endothelial dysfunction, which can exacerbate the growth of atherosclerotic plaques (Münzel et al., 2010). The presence of excessive ROS also promotes the pathological modification of low-density lipoprotein (LDL) into oxidised-LDL after it penetrates the endothelium, which is the first step of atherogenesis (Leopold & Loscalzo, 2008). LDL is a carrier of cholesterol in our blood.
For the case of Alzheimer’s disease, amyloid beta plaque being the main culprit in the pathogenesis of Alzheimer’s disease (AD) has been the reigning hypothesis since the mid-1980s, yet pharmacological approaches that target those plaques seem to be underwhelming (Kametani & Hasegawa, 2018). As a result, research on brain metabolism and energetics has been increasingly attractive as an alternative hypothesis. Astrocytes are supporting cells of the nervous system that receive glucose from the brain, and oxidise it into lactate, to be used by neurons as their primary fuel source (Mason, 2017). Lactate as a fuel source for neurons is essential for long-term memory (Suzuki et al., 2011). Patients with Alzheimer’s disease typically have a diminished capacity to uptake and oxidise glucose in the brain, despite normal blood flow, indicating disrupted mitochondrial function. Likewise, mitochondrial dysfunction may also reduce lactate oxidation in neurons, disrupting neuronal bioenergetics (San-Millán, 2023). Increased levels of inflammation can also activate glial cells in the brain that may suppress neurogenesis and cause cell death (Voloboueva & Giffard, 2011). Cyclophilin D, a protein that causes increased permeability of the mitochondria (Halestrap & Richardson, 2015) has also been found in higher concentrations in the brains of people that suffer from AD brains (Du et al., 2008). Similarly, other neurological disorders are also characterised by dysfunctional mitochondria, such as an increase in the mitochondrial breakdown and defective mitochondrial proteins in Parkinson’s disease (Klein & Westenberger, 2012), as well as increased mitochondrial fragmentation and abnormal PGC-1α, a co-activator of mitochondrial biogenesis proteins, in Huntington’s Disease (Lin et al., 2004).
Non-alcoholic fatty liver disease (NAFLD) more recently renamed to metabolic-associated steatotic liver disease (MASLD) is characterised by a build-up of fat in the liver causing it to be unable to perform its function. It is suggested that a metabolic shift of mitochondria away from fatty acid oxidation causes the accumulation of lipids in liver cells (Zheng et al., 2023). Although there is elevated mitochondrial function in response to the higher lipid availability in MASLD, it is still insufficient to prevent toxicity in the long term. Furthermore, excessive mitochondrial fission may lead to the progression of MASLD, as seen by the rescued MASLD phenotype of mice with artificially induced genetic deletion of mitochondrial fission factor in mice (Hammerschmidt et al., 2019).
Due to the necessity of understanding cancer, the metabolism of cancer cells has been heavily studied, particularly concerning Warburg’s effect. Warburg’s effect describes the observation that cancer cells rely on accelerated glycolysis and produce large amounts of lactate despite having an adequate amount of oxygen (Warburg, 1925). It is hypothesised that this lactate acts as a regulator of carcinogenesis, angiogenesis (production of new blood vessels), immune escape, metastasis, and self-sufficient metabolism, all of which are important for cancer survival (San-Millán & Brooks, 2016). The increase in lactate production led many to posit that cancer has a component that involves injury to the mitochondria. Direct observation of defective mitochondrial structure has also been recorded (Arismendi-Morillo et al., 2017). The excessive production of ROS as a result of defective mitochondria could also upregulate proteins that help cancer cells proliferate and obtain nutrients (Tosatto et al., 2016). Furthermore, mitochondrial DNA mutations are frequently found in cancer cells, with some tumors having exclusively mutated mitochondria DNA (Stewart et al., 2015).
In conclusion, our mitochondria play multiple pivotal roles in the cell aside from being the main energy provider. As a result, impaired mitochondrial function is implicated in various forms of diseases. However, much more research is required in the field to determine the temporality of mitochondrial dysfunction and to innovate novel treatments. In the meantime, let us all appreciate the life we have now, adopt a healthy lifestyle, and keep our mitochondria fit as a fiddle.
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