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Muscle diseases

Sustaining mitochondrial function

München, 12/18/2019

Many rare genetic diseases damage mitochondria, which reduces the supply of energy available to cells, including skeletal muscle cells. Analysis of the proteins in mitochondria reveals how cells boost energy production in response.

Mitochondrial dysfunction in muscle fibers is shown by blue staining (COX-negative). Source: Klopstock group

Mitochondria are intracellular organelles that are often referred to as the cell’s power stations. This is because they are responsible for the synthesis of most of the cell’s principal energy carrier, ATP. The chemical energy stored in this compound fuels cellular metabolism, and it also enables our muscles to contract. Mitochondria are thought to have evolved from bacterial cells that established a symbiotic relationship with a primitive nucleated cell. Although the vast majority of the genes required for mitochondrial function now reside in the cell nucleus, each mitochondrion retains a remnant of its primordial genome. This mitochondrial DNA codes the components required for gene expression in the organelle, as well as 13 proteins that are vital for ATP synthesis. About 350 genetic syndromes are attributable to the loss of mitochondrial function, and some of these syndromes are caused by mutations in the mitochondrial DNA itself. Since muscle fibers consume lots of energy, mitochondrial dysfunction often results in myopathies of various types. For example, chronic progressive external ophthalmoplegia (CPEO) is characterized by gradual paralysis of the muscles required for eye movements. Other syndromes that are caused by mutations in mitochondrial DNA are associated with episodes of epilepsy (MERRF) or recurrent stroke-like episodes (MELAS).

In the case of mutations in the mitochondrial DNA itself, patient muscles often present mosaics of more or less affected muscle fibers. These fibers can be differentiated in histological sections of muscle biopsies with the help of a simple staining procedure. This test is specific for the enzyme cytochrome c oxidase (COX), which plays a central role in the mitochondrial respiratory chain of mitochondria, a set of electron transfer reactions which is essential for the production of ATP.

What then distinguishes COX-positive from COX-negative cells? One possibility is that individual muscle fibers differ in their ability to compensate for the effects of the mutation in mitochondrial DNA. The identification of such a mechanism could open up new therapeutic opportunities for the treatment of patients with mitochondrial dysfunction. To test this idea, a team of researchers led by Thomas Klopstock, Professor of Neurology at the Friedrich Baur Institute (which is part of the Department of Neurology at the LMU University hospital), and Matthias Mann, a Director of the Max Planck-Institute for Biochemistry in Martinsried, made use of two state-of-the-art technologies. First, they used laser-based microscopy to dissect and capture single COX-positive and COX-negative cells from muscle sections obtained from patients with mitochondrial myopathy. They then analyzed the individual fibers with a highly sensitive mass-spectrometric procedure to determine the protein compositions of COX+ and COX− muscle fibers. Their findings have now appeared in the journal Cell Reports.

This approach enabled us, for the first time, to examine in detail how muscle cells react to mitochondrial defects, says Thomas Klopstock. In all, the authors of the new study were able to detect approximately 4000 different proteins in each of their samples. The results revealed that COX-negative cells try to compensate for the reduced functionality of the organelles. They stimulate the cell’s protein synthesis machinery and especially those ribosomes that are engaged in the production of components destined for the mitochondria.

In addition to efforts to mitigate qualitative defects by boosting overall mitochondrial function, the team also detected increased levels of chaperones, molecular machines that facilitate the assembly and insertion of the multiprotein respiratory complexes in the inner mitochondrial membrane. – This presumably represents an attempt to enhance the efficiency of respiration and ATP synthesis.

“Once we understand how the cell’s essential battery – the inner membrane of the mitochondrion – reacts to the loss of power caused by mitochondrial mutations, we may be in a better position to work out how we can reinforce the organelle’s function,” says Marta Murgia, a member of Matthias Mann’s group at the MPI for Biochemistry and first author of the new study.

Klopstock hopes that further studies will help to elucidate the molecular mechanisms that underlie mitochondrial diseases and compromise mitochondrial function. Advances in this area would perhaps allow one to identify possible targets for effective therapies. Indeed, drug candidates that boost the biogenesis of mitochondria are already undergoing preclinical trials.
Cell Reports 2019