Key Learning Objectives
- Learn about mitochondria and their function
- Find out how mitochondrial dysfunction contributes to poor health
- Learn about the many ways mitochondrial protect from and repair damage
- Understand why enhancing mitochondrial quality control supports healthy aging
How Mitochondrial Dysfunction Accelerates the Aging Process
The last few decades have witnessed tremendous developments in the understanding of the aging process. Aging can be broadly described as the progressive, time-dependent deterioration of cellular function caused by the accumulation of cellular damage. Nine characteristics, or hallmarks, of aging have been identified. These hallmarks of aging include things like (1) genomic instability, (2), deregulated nutrient sensing, (3) cellular senescence, etc.[1]
Another characteristic of the aging process, and one that is associated with many of the other hallmarks mentioned above, is mitochondrial dysfunction.[1] Mitochondria are among the first part of the cell to become dysfunctional, especially in metabolically active tissues requiring high amounts of cellular energy like the brain, heart, and muscles. But what are mitochondria?
Mitochondria are specialized cell structures that, among their many functions, are responsible for converting the foods we consume into cellular energy as adenosine triphosphate (ATP). The ATP they produce provides the energy to drive many of the processes in cells, including jobs central to healthy aging.
There are 9 characteristics or hallmarks of aging. One of them is mitochondrial dysfunction.
What Mitochondria do
Mitochondria are a type of organelle—a specialized cellular structure—that participate in a wide range of processes with vital roles in cellular function. Mammalian cells contain a large number of mitochondria, often occupying as much as a quarter of the volume of a cell.
The key function of mitochondria is the generation of cell energy. Cellular metabolism converts carbohydrates, fats, and proteins into energy. It is within mitochondria that the main processes that allow the extraction of energy from nutrients occur. But mitochondria have many other roles: they (1) regulate calcium levels in the cell, (2) participate in heat generation (thermogenesis) in brown fat, (3) contribute to immunity and inflammation, and (4) play a key part in cell survival and cell death pathways. And these are just a few examples!
While making ATP (i.e., cellular energy) is the most well-known job of mitochondria, they do many other important jobs to keep us healthy.
Keeping mitochondria healthy, with proper function and structure, is essential for cells to work optimally. When cells perform well, the tissues they are in are healthier. And when our tissues are healthier, we enjoy better health. From a bottom-up perspective, mitochondrial fitness is essential for our health in general. Because of this, it isn’t a surprise that loss of mitochondrial function is a hallmark of aging and many age-related disorders, whereas maintenance of mitochondrial fitness is linked to increased healthspan and longevity.[1,2]
Why Are Mitochondrial Networks Important?
A single cell can have hundreds to thousands of mitochondria. It’s this network of mitochondria working together that is critical for cellular health and responses to behaviors linked to healthier aging, such as calorie restriction and exercise.
Within each cell, the mitochondrial network is constantly reshaping itself to adapt to our lifestyle and environment. Unfortunately, as we age, mitochondrial number and network performance tend to decline. One result is that we don’t produce enough energy for our cells and tissues to do everything they need to do.
Reshaping of mitochondrial networks is referred to as mitochondrial quality control (MQC) within scientific research. The key thing to remember is that interacting MQC pathways and processes work together to maintain mitochondrial fitness. MQC acts at different levels—molecular, mitochondrial, and cellular—to survey and respond to damage and allow mitochondrial networks to reshape themselves to adapt to diet, lifestyle, and environment.
Cells contain hundreds to thousands of mitochondria. As we age the performance of these mitochondrial networks tends to worsen.
How Do Mitochondria Make ATP?
It’s estimated we make about our body weight in ATP every day. This ATP is often described as being akin to a "molecular unit of currency" of intracellular energy transfer, because it’s how energy to fuel many chemical reactions is stored.
ATP is generated from the catabolism (the metabolic breakdown) of carbohydrates (glucose), fats (fatty acids), and, to a lesser extent, proteins (amino acids). Glucose, fatty acid, and amino acid metabolism converge in mitochondria, where sequential electron transfer reactions (redox reactions, from reduction, the gain of electrons, and oxidation, the loss of electrons) lead to the production of carbon dioxide (CO2) and the extraction of electrons from food.
These electrons are then transferred to electron carriers, the molecules nicotinamide adenine dinucleotide (NAD+; vitamin B3-dependent) and flavin adenine dinucleotide (FAD+; vitamin B2-dependent), reducing them to NADH and FADH2. High-energy electrons move from NADH and FADH2 to oxygen through the electron transport chain in the folds, or cristae of the inner mitochondrial membrane. The movement of electrons is coupled with the transfer of protons (H+) across the membrane to generate the mitochondrial membrane potential that drives ATP biosynthesis. This process of transferring electrons and pumping H+ is called oxidative phosphorylation (often shortened as OXPHOS).
ATP is an energy-rich molecule that releases a large amount of energy when its chemical bonds are broken (yielding ADP); this energy can be used to drive all sorts of cellular processes that need energy input. The vast majority of ATP is produced by mitochondria, which are therefore known as “the powerhouse of the cell.”[3]
Mitochondria are the main site of ATP production and are therefore known as the powerhouse of the cell.
Why a Just Right Amount of Reactive Oxygen Species Is Important
The final electron acceptor in the mitochondrial electron transport chain is oxygen, which is converted into water by binding H+ after receiving the electrons. However, oxygen does not always bind H+, which leads to the generation of superoxide (O2-). Superoxide is a reactive oxygen species (ROS), which is the name given to highly reactive molecules that contain oxygen.[4]
The mitochondrial electron transport chain is the main source of ROS in cells. Superoxide (O2-) is the main ROS generated by the electron transport chain, but it can be enzymatically converted into another ROS called hydrogen peroxide (H2O2). Unlike superoxide, hydrogen peroxide can easily cross membranes and reach other cellular structures. Hydrogen peroxide can be converted into water by different enzymes, but it can also react non-enzymatically to form the extremely reactive hydroxyl radical (•OH), which cannot be eliminated by enzymes.[4]
A side effect or producing ATP is the creation of reactive oxygen species (ROS). ROS can cause cellular and mitochondrial damage if antioxidant defenses are insufficient.
At high levels, ROS cause irreversible damage to cells.[5] ROS increase the oxidation of lipids in cellular membranes (i.e., lipid peroxidation), including mitochondrial membranes, which has a negative effect on their structure and function.[6] Proteins can be oxidized by ROS, leading to protein misfolding and aggregation (note: this is the hallmark of aging called “Loss of Proteostasis”). ROS contribute to another hallmark of aging called “Genomic Instability” by causing oxidative damage to DNA.
Cells have nuclear DNA that passes on the genes from our parents. Mitochondria have their own DNA, the mitochondrial DNA (mtDNA), which encodes a small number of proteins essential for mitochondrial function.[7] mtDNA is particularly susceptible to ROS damage, which can cause the accumulation of mutations that result in an improper synthesis of proteins, having a great impact on mitochondrial physiology. After a certain threshold of mitochondrial damage, cell degeneration ensues, ultimately leading to cell death.[2]
While high amounts of ROS can damage cells and mitochondria, at physiological levels, ROS participate in several signaling pathways, so are important for healthy function. One important function of ROS is to signal mitochondrial stress, which triggers cellular defense responses that promote cellular adaptation and defense mechanisms. This increases cells’ stress resistance, in a process known as mitohormesis, which can have pro-longevity effects.[8,9]
Given their dichotomous roles, a well-calibrated control of ROS levels is essential to avoid the damage caused by ROS accumulation and maintain mitochondrial function. This is where the first level of mitochondrial quality control—antioxidant defenses—steps in.
At high levels, ROS cause irreversible damage to molecules, but at lower levels, ROS trigger responses that promote cellular adaptation and defenses.
How Antioxidant Defenses Keep ROS In Check
One of the mechanisms that help maintain ROS homeostasis is the mitochondrial ROS scavenging system, a powerful antioxidant defense system that forages ROS as they are generated. ROS scavengers are molecules that hunt and eliminate ROS, helping to keep ROS levels low. The mitochondrial ROS scavenging system is made up of small redox proteins and redox enzymes that act not only in mitochondria, but also in other cellular structures.
The enzyme superoxide dismutase (SOD) is responsible for the conversion of superoxide into hydrogen peroxide. There is a cytosolic form of SOD, SOD1 or Cu/Zn-SOD (because it binds copper and zinc), but mitochondria have their own form, SOD2 or Mn-SOD (because it binds manganese).
Hydrogen peroxide (H2O2) can then be eliminated by enzymes that convert it into water (H2O).[10] Enzymatic elimination is important because H2O2 decomposes to hydroxyl radicals, which are particularly damaging. There are several enzymes that are important in the elimination of hydrogen peroxide.
Glutathione peroxidase (GPx) is found in mitochondria and in the cytosol. It eliminates H2O2 with the assistance of the redox molecule glutathione (GSH). Glutathione is a tripeptide made from three amino acids—glutamate, cysteine and glycine. Cysteine is responsible for its biological activity and is the rate-limiting factor in glutathione synthesis.[11,12] Cells can make more GSH if adequate amounts of these three amino acids are in the diet. But because cysteine is rate-limiting, increasing cysteine, typically with the dietary supplement N-acetylcysteine (NAC), is used as a way to boost GSH.[13]
In the GPx enzyme reaction, GSH is oxidized to glutathione disulfide (GSSG), while H2O2 is reduced to water. GSH is then regenerated from GSSG by the enzyme glutathione reductase (GRx) using NADPH (vitamin B3-dependent) as a cofactor. This remakes the GSH, which is then available for new ROS scavenging reactions.
Peroxiredoxins (Prx), also found in mitochondria and in the cytosol, act in a similar way to GPx: they reduce H2O2 with the help of the redox molecule thioredoxin, which is oxidized in the process, being subsequently recycled back to the reduced form by thioredoxin reductase (TRx) using NADPH (vitamin B3-dependent) as a cofactor.
Catalase is very effective at detoxifying large amounts of H2O2, as it can rapidly decompose it into water and oxygen. Catalase is found in a type of cellular organelles called peroxisomes, into which cytosolic H2O2 can easily diffuse.
By acting at the molecular level, the ROS scavenging system is a first line of defense in the MQC network that aims primarily at preventing the occurrence of molecular damage.
Antioxidant defenses include the glutathione molecule and antioxidant enzymes. Working together they scavenge ROS and protect cells from damage.
How Protein Quality Control Keeps Mitochondria Healthy
A second set of molecular MQC processes aims at repairing and restoring the function of damaged proteins, or at replacing irreversibly damaged proteins. This protein quality control (PQC) system is composed of a set of mitochondrial chaperones and proteases, and of cytosolic proteolytic systems that associate with the outer mitochondrial membrane.[14] Chaperones are proteins that assist the folding of other proteins (this is needed to move proteins through cell and mitochondrial membranes). Proteases are enzymes that break down proteins.
Chaperones such as the heat shock proteins HSP22, HSP60 and HSP70 contribute to mitochondrial PQC by sorting and folding misfolded or unfolded proteins back to their native structures, and by disaggregating protein aggregates.[15] They are part of a damage repair system and are a critical component of countering the hallmark of aging called “Loss of Proteostasis” (i.e., protein homeostasis). When the accumulation of damaged or unfolded proteins overpowers the mitochondrial refolding and repairing capacity, the mitochondrial unfolded protein response is triggered; this is a stress response that increases the expression of chaperones and proteases.[16]
Oxidative damage of proteins can be irreversible, meaning the proteins cannot be repaired. Irreversibly damaged proteins have a negative impact on cellular function (they are a core part of the “Aging as Damage Accumulation” theory of aging). Fortunately, cells have a way to deal with this issue. Irreversibly damaged proteins can be eliminated through proteolysis—the breakdown of proteins. This is achieved through the proteolytic PQC system, in which mitochondrial proteases and cytosolic proteolytic systems like the ubiquitin–proteasome system (UPS) degrade damaged or aggregated proteins. These are then replaced by new proteins produced by de novo biosynthetic pathways.[15]
PQC also occurs at the mtDNA level by a set of mitochondrial DNA repair pathways that find and correct mtDNA mutations. This mechanism assures that the integrity of the essential proteins produced from mtDNA is maintained.[17]
Accumulation of damaged proteins contributes to aging. The protein quality control system repairs reversibly damaged proteins and replaces irreversibly damaged proteins, essentially cleaning up and recycling junk proteins in our cells.
How Mitochondrial Networks Reshape Themselves
Mitochondria are not inert and isolated organelles, they are connected and form a dynamic network. This network is constantly being reshaped to better adapt to circumstances. Mitochondria change their shape, size, and position within the cell, in a process known as mitochondrial dynamics, driven by two opposing forces called fusion and fission.[18]
Mitochondrial fusion allows two adjacent, smaller mitochondria to merge and form a larger and more elongated mitochondrion. This merging strategy can be used when cells need fewer mitochondria (i.e., a smaller network). Larger, elongated mitochondria are more efficient in the generation of cell energy, whereas smaller, spherical mitochondria are more easily transportable and distributable during cell division.[19]
Mitochondrial fusion is also a damage control and repair strategy. One way to minimize the contribution dysfunctional mitochondria make to the network is to have them merge with more functional mitochondria. After fusion occurs, the damaged mitochondrion is no longer operating on its own, and some of the damage or dysfunction might be repaired by using capacities from the undamaged mitochondrion.[20] When fusion is used as a damage control strategy, the network might be sacrificing some of the performance of the more functional units but does this to get rid of or repair the poorly performing dysfunctional mitochondria.
Mitochondrial fission is the opposite of fusion. Fission generates two smaller mitochondria. Fission is essential for mitochondrial duplication and biogenesis (i.e., the creation of new mitochondria). It’s also required for cell division. And, similar to fusion, fission plays a role in damage control because it allows for the segregation of damage. Mitochondrial content can be mixed and separated, allowing the isolation of damaged molecules or structures. Then, through mitochondrial fission, smaller mitochondria with different properties can be generated, separating the damaged from the functional.[18] A damaged mitochondrion may recover and fuse with another mitochondrion, but if the damage is irreparable, it will be degraded (i.e., the mitochondrion will be eliminated).[21]
The balance between mitochondrial fusion and fission is essential for the maintenance of a healthy mitochondrial network. When fusion-fission processes are performing in a coordinated manner, mitochondrial damage is isolated and repaired, and the overall performance of the network is maintained at a high level.[14] Mitochondrial dynamics—the dance of fusion and fission—allow a cell’s mitochondrial network to make enough ATP to meet demands, while also ensuring that the ROS created are at a level that can be dealt with by antioxidant defenses.
Mitochondrial dynamics—fission and fusion—play an important part in isolating and repairing mitochondria so they can make more ATP.
How Mitochondria Get Rid Of Irreversible Damage
Autophagy (literally ‘self-eating’) is a process by which a cell degrades and recycles its own contents, particularly damaged proteins and organelles, for cellular renovation and homeostasis maintenance.[22] Aging as a process of damage accumulation is one of the main theories of aging. By cleaning up cellular debris and preventing it from accumulating, autophagy helps keep cells performing at a younger level.
Mitophagy (mitochondrial autophagy) is a specific type of autophagy that selectively degrades damaged mitochondria. It is a tightly regulated MQC process that acts at the organellar level.[14] Non-selective autophagy and selective mitophagy are of great biological relevance because they allow the elimination of irreversibly damaged and dysfunctional mitochondria that have been segregated by mitochondrial fission.[23]
During mitophagy, damaged mitochondria are engulfed by autophagic membranes, leading to the formation of a vesicle called autophagosome. They are then fused with lysosomes, a type of organelle that contains enzymes that degrade biomolecules, forming an autolysosome, in which mitochondria will be degraded, with their breakdown products being made available for cellular metabolism.[22]
Mitophagy is a process by which damaged mitochondria are degraded and recycled.
How Mitochondrial Networks Get Fitter
Mitochondrial biogenesis is the generation of new mitochondrial content. It is the opposite of mitophagy. Together, biogenesis and mitophagy are complementary, in a sense acting as the equivalent of birth and death processes for the mitochondrial populations within cells.
New mitochondria are produced from pre-existing ones through fusion and fission events, by adding new mitochondrial proteins, and extending the mitochondrial membranes. Mitochondrial biogenesis is, effectively, an increase in mitochondrial mass.[24]
Mitochondrial biogenesis is a complex process that requires the replication of mtDNA, transcription and translation of mtDNA and nuclear DNA genes, membrane recruitment, protein import, protein allocation to different mitochondrial subcompartments, and assembly of the oxidative phosphorylation complexes. All this is carried out in coordination with the existing mitochondrial network.[25]
Mitophagy and mitochondrial biogenesis share signaling pathways and work in a coordinated mode to remove damaged mitochondrial material and add new functional mitochondrial mass; they create a cycle of degradation and replenishment of mitochondria that acts to maintain optimal mitochondrial functionality. The balance between these two processes determines the mitochondrial content of cells and allows the adjustment of mitochondrial mass in accordance to the cells’ energy requirements.[25]
Mitochondrial biogenesis increases the mass of the mitochondrial network in a way that is a bit akin to how muscles get bigger from lifting weights. It is a mitochondrial fitness process.
Why MQC is Essential for Healthy Aging
Some degree of damage occurs as part of normal metabolism. Because of this, mitochondria have evolved a variety of interconnected processes, collectively called mitochondrial quality control (MQC), to (1) minimize it, (2) repair what does occur when possible, and (3) when not possible, get rid of the damage. It’s thought that one of the reasons cells age, (and hence we age) is because MCQ can’t keep pace.
During aging, damage to molecules and mitochondria cannot be entirely prevented, repaired, and eliminated because MQC processes have limited capacity. Therefore, there is a slow buildup of damage that affects mitochondrial function. As mitochondria become less efficient in producing cell energy, they produce higher levels of ROS, which increases oxidative stress and further increases mitochondrial dysfunction.[26,27]
Efficient mitochondrial quality control slows down the natural age-related buildup of damage that affects mitochondrial function.
At the same time, there is also a natural age-related decrease in the efficacy of antioxidant defenses and other MQC processes, which accelerates cellular senescence and ultimately affects the whole physiology of tissues and organs. It’s a snowball effect that is particularly detrimental to high‐energy‐demanding tissues such as muscles, brain or heart.[28–30]
Still, the rate of damage accumulation can be reduced by optimizing MQC mechanisms. Supporting MQC can help mitochondria to help themselves. Mitochondrial networks are capable of upregulating antioxidant defenses, repairing or replacing damaged molecules, reshaping themselves to more efficiently produce ATP, and managing the mitochondrial populations through mitophagy and biogenesis.
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