BETA

What Are Mitochondria?

Mitochondria are organelles, tiny structures inside cells that use oxygen to transform energy from the food we eat into an electrical potential that powers complex life. In addition to this essential job, mitochondria play important roles in dozens of cellular processes, ranging from producing important cellular building blocks, synthesizing and receiving stress hormone signals, and even regulating programmed cell death. In textbooks, they’re usually portrayed as singular bean-like blobs with a squiggly inner membrane, but they don’t appear that way in actual cells. Mitochondria exist as a dynamic network inside each cell in the body and can break apart or fuse together in long chains in response to the changing demands of the cell. Mitochondria move around the inside of the cell to perform their functions where they are needed, and can travel between cells during times of stress.

The well-known textbook cell model depicts mitochondria as static jellybean-shaped organelles sparsely distributed throughout the cell. Image by storyset on Freepik
This cell model is sharply contrasted by the sprawling morphology of the mitochondrial network (labeled red) as seen in a human skin fibroblast cell imaged using fluorescence microscopy.
We present an updated cell model more accurately illustrating the branching morphology of the mitochondrial network, showing the diversity of long, fused mitochondria along with short, punctate mitochondria within the cell.

Mitochondrial Genetics

Unlike the 23 pairs of nuclear DNA chromosomes that a person inherits from both of their parents, the mitochondrial DNA is inherited exclusively from the mother’s egg cell. Each egg cell can contain more than 100,000 copies of mitochondrial DNA. Outside of rare exceptions, all of the sperm mitochondria are degraded after fertilizing an egg cell, leaving only those mitochondria from the mother’s egg cell in the new zygote.

Mitochondrial Biogenesis and Quality Control

New mitochondria in cells form when existing mitochondria build more proteins and replicate their DNA, and then divide to form two mitochondria from the original, larger one in a process called mitochondrial biogenesis. Old, damaged mitochondria, on the other hand, are broken down through a process called mitophagy. Mitophagy is a natural, ongoing process in which the cell identifies mitochondria that have lost their capacity to transform energy and fuses them with lysosomes. These lysosomes have very low pH and digestive enzymes to break down and then recycle the mitochondrion’s building blocks to make new cellular components.

Where Are Mitochondria Found?

Mitochondria exist inside every cell and platelet in the body except red blood cells. The number of mitochondria in an individual cell can change in response to diverse signals, due to their ability to replicate and mark themselves for recycling. For example, exercising can trigger your muscles to produce more mitochondria. Still, on average, different tissues and cell types seem to have different set points for mitochondrial content. Researchers are working to understand how cells “know” how many mitochondria to have.

Parts that Make Up Mitochondria

Mitochondria have two membranes, the outer mitochondrial membrane and the inner mitochondrial membrane. The inner membrane surrounds the mitochondrial matrix, and the space between the two membranes is called the intermembrane space. These two membranes contain hundreds of membrane-bound proteins that serve unique functions in the mitochondria. Of special interest, the outer membrane contains receptors for a multitude of cellular and hormonal signals that alter mitochondrial activity to allow the cell to respond to the signaled information, and the inner membrane contains the machinery of the electron transport chain. Each of the membranes has different permeability. Salts, metabolites, and small proteins can get cross the outer membrane, but can’t cross the inner membrane without the aid of molecular transporters. Besides the nucleus, mitochondria are unique among animal organelles and cellular structures because they possess their own genome. The mitochondrial DNA (mtDNA) is regulated and replicated independently of the 23 nuclear chromosomes. Still, most of the 1100–1400 proteins that exist in the mitochondria are encoded by the nuclear DNA and imported into the mitochondria, with the mitochondrial DNA encoding for only 13 proteins.

Mitochondrial DNA Vs Nuclear DNA

Mitochondrial DNA is somewhat different from the nuclear DNA that most people are familiar with. Both genomes are composed of the same chemical building blocks and form the famous double helix structure. However, unlike the linear nuclear DNA that forms chromosomes, the mitochondrial mtDNA is circular like a bacterial genome and is bundled a few copies at a time into structures known as nucleoids. The human mitochondrial DNA is quite small, containing only 37 genes, 13 encoding proteins, with the remaining encoding 22 tRNAs and 2 rRNAs. In contrast to the more than 20,000 genes in the nuclear genome, the mitochondrial DNA is tiny. Each nucleated human cell contains only two copies of each nuclear chromosome, while cells can contain hundreds and even thousands of copies of mtDNA. Lastly, while we inherit our nuclear genes from both parents, mitochondrial DNA is inherited exclusively from our mothers outside of exceedingly rare occasions in which mutations lead to mitochondrial DNA inheritance from both parents.

What Mitochondria Do

Mitochondria play many roles in the body. Their best-known job is using oxygen to transform energy from food into an electrical potential across the mitochondrial inner membrane that cells use to do work. To accomplish this feat, the mitochondria employ a group of four protein complexes (notated complexes I-IV) seated in the inner membrane. Together, they’re called the electron transport chain (ETC). The ETC harnesses energy from chemical bonds in the food we eat to pump protons, or hydrogen ions, into the inner membrane space of the mitochondria. This generates an electrical potential and a proton gradient that can flexibly drive several essential cellular processes that keep the cell alive and healthy. Electrons extracted from the chemical bonds in sugars, fats and proteins by glycolysis and the Krebs cycle enter the chain through either complex I or complex II in the chain, which are carried to complex III and finally to complex IV. Complexes I, III, and IV pump protons across the inner membrane into the intermembrane space when electrons flow through them. Complex IV facilitates a chemical reaction between transferred electrons, molecular oxygen from the air we breathe, and hydrogen ions to form water. When this happens, new electrons enter the chain to replace those that have now formed water molecules pulling the cycle forward.

As this process continues, the intermembrane space holds far more protons than the matrix. The difference in proton level across the membrane produces an electrical charge called the mitochondrial membrane potential. This membrane potential stores energy which is used to drive a variety of cellular processes. Most famously, the potential drives the process called Oxidative Phosphorylation (OxPhos) which is how mitochondria produce ATP, the energy currency of the cell! Protons pumped into the intermembrane space can enter a channel in the protein complex called ATP synthase or complex V (five). As these high energy protons flow through ATP Synthase, a protein subunit of the complex physically turns like a mechanical water wheel. As it turns, it harnesses the energy stored in the mitochondrial membrane potential to generate ATP. Of course, mitochondria function as networks instead of individuals. The mitochondrial network responds almost instantaneously to the changing energetic needs of the cell and regulates its metabolic state to supply the cell with the chemical building blocks and ATP is requires at any given time.

Calcium Transport & Other Cardiac Functions

Mitochondrial dysfunction is implicated in heart attacks and the transition to heart failure. One of the ways that mitochondria influence heart function is by regulating calcium transport across the inner membrane. Calcium is a critical and potent cellular signal. In sensitive cardiac muscle cells, specific levels of calcium help the heart contract, but too much free calcium can lead to cell death. The ability of the mitochondria to regulate cellular calcium levels depends on the mitochondrial membrane potential, and researchers are actively studying the myriad mechanisms by which mitochondria influence cardiac function. Of course, the heart requires a lot of energy to pump continuously, and if mitochondria cannot meet demand, the heart will not function properly.

Immune System Regulation

Mitochondria regulate immune function in multiple ways. The organelles can activate inflammatory pathways, and regulate both the growth and differentiation of different types of immune cells.

Determine Cell Differentiation

Before cells turn into bone cells, blood cells, skin cells, brain cells, fat cells or any other type of cell with a particular and specialized function, they start as stem cells, with the potential to become many different types of cells. A variety of molecular signals help to direct a cell where to go and how to develop so that it will be able to perform a specialized function. The fusion and fission of mitochondria, which regulate molecular signaling pathways, play a major role in determining the fate of a stem cell.

Epigenetics

Epigenetics is the study of how behaviors and environment can influence gene expression. While genes typically don’t change, mitochondria create chemical compounds that can attach to the DNA and influence its activity. These changes have wide ranging effects. For example, different epigenetic patterns can raise or lower an individual’s risk of developing cancer.

How Mitochondria Communicate

In addition to sending and receiving molecular signals through the cell, mitochondria communicate directly with one another by forming networks through which they can transfer chemicals and proteins.

Fusion

Mitochondria can fuse both their inner and outer membranes and create connections among themselves. Through these connections, they can share chemical signals to guide their function and even proteins that can help rescue dysfunctional mitochondria.

Nano tunnels

Rather than fusing, sometimes mitochondria join their membranes and form long, narrow tunnels through which they can transfer substances. The process is often referred to as “kissing and running.”

Aligning Cristae

Mitochondria can also line up their inner membrane folds, or cristae, with those of other mitochondria. Scientists suspect that this allows electrochemical signals to flow like a wave through the network of mitochondria.

What Causes Mitochondrial Dysfunction?

Primary Mitochondrial Diseases

Primary mitochondrial diseases are caused by genetic mutations. Those mutations can exist in either the nuclear DNA or the mitochondrial DNA, but they affect proteins directly involved in the process of transforming food and oxygen into usable energy in the cell.

Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-Like Episodes (MELAS) Syndrome

MELAS is one of the better understood primary mitochondrial diseases. It’s caused by a point mutation in the mitochondrial leucine tRNA-encoding gene. tRNAs are the structures that bring amino acids to the ribosome when synthesizing new proteins. As a result of this mutation, any protein that includes leucine will have functional problems. The disease tends to be both severe and progressive, causing serious neurological impairment by young adulthood.

Secondary Mitochondrial Diseases

Secondary mitochondrial diseases are those that involve abnormal mitochondrial function, but that are caused by environmental effects or mutations in genes that are not directly related to the mitochondrial energy transformation. Like primary mitochondrial diseases, these conditions can have wide-ranging symptoms that impact affect systems throughout the body.

Mitochondrial Involvement in Common Diseases

Even when mitochondrial dysfunction isn’t the underlying cause of disease, it’s often involved. Many common diseases are characterized by mitochondrial dysfunction. Here are just a few examples of diseases in which scientists have found abnormal mitochondrial behavior.

Diabetes

In those with type 2 diabetes, mitochondrial networks appear to be fragmented more frequently than not. The organelles produce less ATP. Some research has found that interventions to improve mitochondrial function also reduce insulin resistance in diabetes.

Obesity

In people with obesity, researchers have found reduced mitochondrial activity and smaller mitochondrial networks in the skeletal muscles.

Alzheimer’s disease

People with Alzheimer’s disease have less ATP in their neurons than healthy individuals, a sign of metabolic and potentially mitochondrial dysfunction. Mitochondrial networks also appear to be disrupted in Alzheimer’s disease.

Getting Diagnosed with a Mitochondrial Disease

Mitochondrial disease experts are dispersed, and many patients can be misdiagnosed at first. Specialists typically diagnose patients, based on mitochondrial disease criteria (MDC) scoring systems. These include Nijmegen, modified Walker, Morava criteria and others. They not only assess visible symptoms, but also a variety of laboratory findings that help the specialist determine whether a patient definitely, probably or possibly has a mitochondrial disease, or if it can likely be ruled out. In some cases, doctors can use muscle biopsies, genetic test or other molecular markers in the blood and urine to diagnose or confirm mitochondrial diseases.

Lifestyle Factors that Influence Mitochondria

Exercise

Exercise increases the quality and quantity of mitochondria, especially in heart and muscle cells. Exercise also seems to induce mitochondrial fusion, leading to more surface area of the cristae and elevated mitochondrial output capacity. This may be one of the reasons that exercise helps with so many conditions, such as obesity and type 2 diabetes.

Stress

Short-term acute stress may damage mitochondria briefly, but allow them to regenerate and become stronger, much like how your muscles are exhausted immediately after a workout but grow in response to exercise. However, chronic stress seems to lead to a variety of mitochondrial disfunctions.

How Mitochondria Change as We Age

The rate at which we age may be coordinated by several biochemical pathways involved in mitochondrial physiology. There are multiple theories about how exactly mitochondria change with age, and how that affects human health, but the organelles are well-known to show dysfunction in many age-related diseases, such as dementia, type 2 diabetes, hypertension, and chronic inflammation.

Glossary

ATP: adenosine triphosphate, a compound that stores energy inside cells.

Chromosome: a physical structure made of DNA and proteins that protects, organizes and regulates access to the genetic material. The human nuclear genome is stored in 23 pairs of chromosomes.

Electron: a particle within an atom bearing a negative electric charge.

Glycolysis: the multi-step metabolic reaction performed outside of the mitochondria that breaks down glucose, releasing energy and forming chemical building blocks that cells use as important signals and raw materials to assemble new parts.

Leucine: an essential amino acid that helps muscles function.

Lysosomes: acidified organelles that contain digestive enzymes. Lysosomes help cells break down waste and damaged cellular components.

Mitochondrial Intermembrane space: the space between the inner and outer membranes of the mitochondria.

Mitochondrial Matrix: the space inside the inner mitochondrial membrane.

Mitochondrial Membrane Potential: the difference in electrical charge across the mitochondrial inner membrane. This potential stores energy that the mitochondria can use to produce ATP and perform other functions.

Nuclear genome: DNA inherited from an individual’s mother and father stored inside the nucleus of cells. The human nuclear genome encodes approximately 20,000 genes that hold the information to make up to 100,000 different proteins.

Organelle: a structure within a cell that serves a specialized function, much like an organ in the body.

Programmed cell death (apoptosis): the coordinated biological program by which a cell kills itself. This can occur in many different situations, such as when the cell is no longer needed by the organism, if it has become infected with a virus, or it is recognized as cancer by the immune system. The molecules that trigger programmed cell death are stored within the mitochondria, and releasing them into the cell is the first step of apoptosis.

Protein complex: a group of two or more proteins that work together to perform their function like the individual gears in a watch. Mutations in the proteins that form a complex can change how the individual parts work together, altering or knocking out the function of the whole complex.

Zygote: a fertilized egg that can replicate to form an embryo.