Economic Solutions: Mitochondria

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October 3, 2016

Why Three-Parent Babies Could Help Restore Health to the Aged

Dear TransTech Reader,

You may have seen recent headlines about the birth of a three-parent baby. The process used a technique pioneered by John Zhang of the New Hope Fertility Center in New York. While not the first baby born with genetic materials from three people, it was the first birth using unfertilized human eggs or ova.

To do this, the DNA in the genome of a healthy donor’s ovum is removed. Next, it is replaced by the mother’s DNA using spindle nuclear transfer. The modified ovum is then fertilized with the father’s sperm.

The purpose of the procedure is fairly simple. Some women have mitochondria that are so mutated that the offspring’s health is endangered. Using a donor’s ovum provides the resultant child with healthy mitochondria.

Mitochondria are one of the most fascinating aspects of biology. All multi-cellular organisms, including humans, have cells that contain subunits (organelles) bound by membranes. The primary organelle is the nucleus. It contains the massive DNA genome, which is the master program that runs the animal’s biology.

But there is another organelle that contains its own DNA… mitochondria. They have at least one circular ring of DNA called a plasmid. Compared to the DNA in a cell’s nucleus, mitochondrial DNA is quite basic. In humans, mitochondrial plasmids have 37 protein-encoding genes and about 16,500 base pairs.

The master genome is much bigger with about 20,000 genes that encode proteins. But this number grossly underestimates the complexity of the genome, which consists of about 3 billion base pairs.

The nearly 99% of DNA that does not produce proteins was once considered “junk DNA.” Today, we are just starting to understand the profound influence that non-coding DNA has on the regulation of genetic activities.

Though the DNA in mitochondria is simple, we have a lot of it. Each cell has on average about a hundred mitochondria, and each may contain multiple plasmids. Clearly, this means you were lied to when you were told that half of your DNA comes from your mother and half from your father.

This is true of the genome (the DNA in the nucleus of the cell). But all the mitochondrial DNA in all of your cells came from your mother’s ovum. The mitochondria in your cells today came directly from mitochondria in the egg you came from. In fact, it was in that egg even before it was fertilized and became an embryo. So it would be more accurate to say that one third of your DNA came from your father.

Mitochondria have a lot in common with bacteria

Mitochondria, like bacteria, pass information among themselves. They also adapt as a population to different conditions. This isn’t surprising because mitochondria are, in essence, bacteria tailored to live inside your cells.

Also like bacteria, mitochondria multiply via fission. A single mitochondrion separates into multiple mitochondria. Each is equipped with at least one plasmid ring of DNA.

It was once thought that mitochondria were like isolated robots… taking orders from the cell’s central genome. But, mitochondria in a healthy animal are a second form of genetic intelligence. They communicate with each other as well as the genome. You could view the vast system of quadrillions of mitochondria in your body as a kind of alien symbiosis. In fact, mitochondria are sometimes classified as endosymbionts, organisms that live within another organism.

The primary and most-studied function of mitochondria is energy production. Only mitochondria can convert food into usable biological energy (adenosine triphosphate or ATP). As such, our mitochondria make up an intelligent energy grid. They respond to the differing needs of our diverse cell types under ever changing conditions.

Unlike bacteria in the wild, mitochondria are specialized. They depend on the central genome to detect and fix their problems. And here’s where the symbiosis can break down.

Due to their genetic simplicity and dependence on the central genome, mitochondria have a faster pace of genetic mutation. Since they age faster than the genome, this can throw an otherwise healthy system into chaos.

Sometimes, mutations disrupt the communications network and are passed down to subsequent generations. About one child in a thousand is born with some sort of serious mitochondrial mutation. About one in 4,000 has a potentially life-threatening disease.

In the case I discussed above, the mother’s mitochondria were so flawed that her first two children died. John Zhang solved this problem by injecting her DNA into another woman’s ova, which had healthy mitochondria. It was then fertilized using standard IVF to create a healthy child without mitochondrial disease.

So why does this matter to the field of anti-aging medicine?

Mitochondrial mutation drives the aging process

More and more, this faster mutation rate of mitochondria is seen as a driver of accelerated aging. We all experience this type of mutation. When we’re young and conditions are perfect, the genome may be able to stop replication of mutated mitochondrial plasmids.

As we age, though, these endosymbionts may not be able to cope. This starts a cascade of failures that leads to age-related disease and death. As such, mitochondria may be the weakest link in the chain of healthy aging.

In the past few years, several promising molecules have been found that improve conditions for mitochondrial communication and function. I’ve written a great deal about nicotinamide riboside and oxaloacetate. Both are naturally occurring molecules that are vital to mitochondrial function. Supplementation boosts energy production and aids the communications between genome and mitochondria, so both compounds are therapeutic candidates for various age-related diseases.

Other promising compounds are also being studied. One is humanin, a peptide-signaling molecule manufactured naturally by mitochondria. Humanin production decreases as we age, but supplementation in multiple animal trials shows it protects neurons from stress and apoptotic cell death. This includes damage caused by the amyloids linked to Alzheimer’s.

It has also shown benefits in retinal diseases, type 1 and type 2 diabetes, cholesterol-related vascular problems, as well as strokes and heart disease. In short, it appears to be a systemic anti-aging compound. I’ll have more on this in the future, but here is a good introduction.

Another recent finding has to do with the long-running controversy about free radicals. Scientists refer to them as reactive oxygen species (ROS). ROS are used by the immune system to fight certain diseases. But chronic overproduction of ROS (especially hydrogen peroxide) is a major cause of autoimmune disease. We now know that most of the excess production of ROS occurs in mitochondria.

This makes sense because mitrochondria act like biological batteries. They produce energy by exploiting the potential of two separate compartments with an imbalance of electrons. Leakage of electrons from the electron transport chain creates superoxides. These then become free radicals or ROS.

Several compounds now being tested greatly reduce the excess production of ROS without harming the immune system’s ability to ramp up ROS production when it’s needed. An important journal article on this topic is online here. Though this article doesn’t talk about it, some of the authors have been researching natural compounds that significantly solve the superoxide problem. I’m convinced that this is one of the most important breakthroughs in anti-aging medicine.

The “mitochondria as battery” metaphor works quite well when trying to understand the problems we have with these fast aging endosymbionts. As my molecular biologist son observed: “What’s the first thing that fails on your laptop?”

The answer is the battery. Fortunately, I think we’re close to understanding how to fix those problems.