“Mitochondria are the result of a 1.5 billion-year-old fusion event between bacteria and early eukaryotic cells. These essential organelles, found in almost every cell in our body, are required to convert nutrients into usable energy. Indeed, the mitochondrial oxidative phosphorylation (OXPHOS) system produces the majority of cellular energy in the form of adenosine triphosphate (ATP). ATP is the currency of energy – we use 70 – 200 kg of ATP per day,” said Joanna Rorbach, Department of Medical Biochemistry & Biophysics at the Karolinska Institute, Stockholm, Sweden. “While it is certainly true that mitochondria are cellular powerhouses, the field of mitochondrial biology has undergone a major transformation over the past two decades. The simplistic concept of these organelles as kidney bean-shaped power plants has given way to one of a dynamic and complex sub-cellular network that orchestrates a vast array of processes central to cellular life and death.”
The process of ATP manufacture in mitochondria was described in the 1950s and 60s by Peter Mitchell (winner of the 1978 Nobel Prize for Chemistry) and later Paul Boyer and John Walker (winners of the 1997 Nobel Prize in Chemistry) and, said Rorbach, “We thought the understanding of mitochondria was solved but we came to realise it was associated with 100s of other processes”.
“I’ve spent almost two decades working in metabolism, mitochondria and aging,” continued Rorbach, who is both a STIAS and Wallenberg Academy Fellow. “As an undergraduate student, I was interested in understanding neurodegenerative-disease mechanisms and at that time research started to show that mitochondrial dysfunction play an important role in neurodegenerative pathologies. But we are still only scratching the surface. It will keep me and others busy a lot longer.”
All more complex organisms including animals, fungi, plants and humans have mitochondria. They are tiny organelles and there are 1000s of copies in our cells. They were described first by Richard Altmann in 1894. Rorbach explained that within our cells, we have two genomes, the nuclear genome inherited from both of our parents (which contains the majority of our genes), and the mitochondrial genome (mtDNA, encoding critical components of the OXPHOS machinery), which is maternally inherited; “With Mitochondrial Eve who originated in the palaeo wetlands of southern Africa about 200 000 years ago the ancestor of all.”
The nuclear and mitochondrial genome’s cannot survive without each other but the vital role and multiple functions of mitochondria as hubs for the cellular-metabolism pathways has become much clearer over the past few decades.
“Almost all metabolic pathways in the body go through the mitochondria,” said Rorbach. “Mitochondria have multiple roles including ATP production, programmed cell death, stem-cell reprogramming, innate immunology, biosynthesis and calcium homeostasis. They are important for many different developmental processes in the body and for fighting pathogens.”
“They are also highly dynamic – not a single floating structure but constantly changing networks – exchanging information within the networks and moving all the time.”
“What gives people power?” laughed Rorbach, “– simple, mitochondria, status, money.”
Not the end of the story
Unfortunately, there is also a downside, as mitochondria are linked to both genetic diseases caused by genomic mutations as well as more common non-communicable diseases caused by mitochondrial dysfunction.
“Given the evolutionarily ancient role of mitochondria, which many posit facilitated multicellular life, it is unsurprising that defects in mitochondrial function can result in clinically severe diseases,” explained Rorbach. “Typically, mitochondrial diseases affect organs and tissues with a high metabolic demand, such as the nervous, muscular, cardiac, endocrine and immune systems. Such conditions are highly heterogeneous from a clinical and molecular viewpoint, complicating treatments and worsening prognoses. Mitochondrial dysfunction has also emerged as a key factor in many common diseases, such as cancer, type-2 diabetes, Parkinson’s disease and Alzheimer’s disease, while mitochondria are routinely linked with the ageing process.”
Mitochondrial diseases can affect more than one organ and at different life stages. There are no cures, just treatments to alleviate symptoms. “They are hard to diagnose,” said Rorbach. “And obviously very distressing in children. We are trying to understand them better.”
Mitochondrial diseases are usually diagnosed via muscle biopsy and genetic sequencing. “Different genes are linked with different disorders and the same mutation in different people can cause different symptoms.”
And they are not that rare – about one in 5000 people has an inherited mitochondrial disease. “Mutations have been found all over the world,” continued Rorbach. “Thanks to the development of robust genome-sequencing technologies, databases are being built that are revolutionising understanding of mitochondrial disease.”
Novel gene therapies
She described a study she was involved during her postdoctoral studies involving a woman who had lost eight children to a mitochondrial-related disease not realising it was passed from her and who is now an advocate for studies on mitochondrial diseases.
There are now novel gene-therapy approaches including the so-called ‘Three-person baby’ strategy to prevent transfer of genetic defects. “In this approach the mother’s nucleus is removed and placed into a healthy donor egg – it still means the baby has more than 99% of the mother’s and father’s DNA but the unhealthy mutation is removed,” explained Rorbach. Of course, this was initially controversial with ethical and religious arguments against genetic manipulation as well as concerns around safety and compatibility but the science showed it worked and Britain was the first country to allow this by law in 2015. “We know the technology works, said Rorbach, “but, of course, it needs proper controls.”
Other novel therapies include the use of Zinc finger nucleases – tools that allow targeted editing of the genome discovered by Aaron Klug (who grew up in South Africa and was awarded the 1982 Nobel Prize for Chemistry). “We have adapted techniques to target mitochondrial mutations – effectively cutting off the bad DNA,” said Rorbach. “This works in animal models but there are many years of development before it reaches humans.”
New technologies are shaping fundamental advances helping us decipher the genetic and molecular basis for these debilitating conditions. Technologies including Nuclear Magnetic Resonance, cryogenic electron microscopy and X-ray crystallography are continually increasing understanding of mitochondrial DNA and RNA metabolism, protein synthesis and the role of mitochondrial ribosomes, as well as the disease-related clinical consequences of all of this and how it might be possible to block and stop some of these processes. Increased imaging abilities have made it possible to develop 3D models and to see changing states over time and better computational power makes it possible to generate data much faster.
“Twenty years ago it cost more than $100 million to sequence one human genome, now the cost is less than $1000. It can be done in 24 hours and mutations can be discovered quickly which means, although we can’t cure, we may be able to prevent some symptoms.”
Studies are also looking at the effects of newer viruses and pathogens “For example,” explained Rorbach, “it wasn’t clear how COVID-19 would affect patients with these conditions and also the effect of new vaccination strategies.”
But, warned Rorbach, all these studies are long term and, critically, never based around one laboratory but require multi-centre, multi-country collaborations.
“Despite huge advances, our understanding of the mechanisms governing mitochondrial function and associated pathologies remains limited, complicating clinical management and therapeutic development.”
In discussion, she was asked about the existence of ‘Y chromosome Adam’ who may have existed more than 150 000 years ago, as well as the use of mitochondrial DNA science in the development of anti-ageing beauty products.
“Most of the work is still experimental even in the developed world,” she said. “Gene therapies take time and money.”
Michelle Galloway: Part-time media officer at STIAS
Photograph: Anton Jordaan