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Mitochondrial diseases: the contribution of organelle stress responses to pathology

Key Points

  • Defects of mitochondrial DNA (mtDNA) maintenance and mitochondrial translation (mtDNA gene expression defects) are the most common causes of mitochondrial disease, which was revealed by next-generation genetic tools. These disorders can be caused by mutations in nuclear or mtDNA genes.

  • The diversity of clinical manifestations of mtDNA gene expression diseases, which affect numerous tissues and can have a variable age of onset, cannot be explained only by a deficiency of mitochondrial ATP synthesis. Recent evidence indicates that various mitochondrial defects elicit specific stress responses, which affect both catabolic and anabolic metabolism at the organelle, cell and tissue level, and even signalling to the whole organism.

  • Different types of mitochondrial stress require specialized local and whole-cell quality control mechanisms to rectify the stress and the potential insult that could result from that stress. Deregulation of these quality control mechanisms can also contribute to disease.

  • Activating transcription factors (ATFs) are highly conserved regulators of mitochondrial stress responses and have been implicated in the remodelling of cellular as well as whole-body metabolism during mitochondrial dysfunction.

  • Evidence from mouse models of mitochondrial diseases indicates that targeting metabolism may offer promising therapies for treating patients with mitochondrial disorders.

Abstract

Mitochondrial diseases affect one in 2,000 individuals; they can present at any age and they can manifest in any organ. How defects in mitochondria can cause such a diverse range of human diseases remains poorly understood. Insight into this diversity is emerging from recent research that investigated defects in mitochondrial protein synthesis and mitochondrial DNA maintenance, which showed that many cell-specific stress responses are induced in response to mitochondrial dysfunction. Studying the molecular regulation of these stress responses might increase our understanding of the pathogenesis and variability of human mitochondrial diseases.

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Figure 1: The variability of mitochondrial disease manifestations.
Figure 2: Mechanisms of mtDNA replication and translation highlighting factors implicated in human disease.
Figure 3: Genes that encode components of the mtDNA maintenance and expression machineries and that are associated with human mitochondrial disorders.
Figure 4: Stress responses in mitochondrial dysfunction.

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Acknowledgements

The authors would like to acknowledge the Academy of Finland, the University of Helsinki and the United Mitochondrial Disease Foundation USA (A.S. and B.B.), and the Sigrid Jusélius Foundation, the European Research Council and the Jane and Aatos Erkko Foundation (A.S.) for their support, and members of the FinMIT Centre of Excellence in Research on Mitochondria, Metabolism and Disease for their contributions and stimulating discussions.

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Correspondence to Anu Suomalainen or Brendan J. Battersby.

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Supplementary information

Supplementary information S1 (table)

Nuclear genes causing disorders of mitochondrial DNA maintenance and translation, genetic basis, phenotypes. (PDF 220 kb)

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Figure 3 abbreviations (PDF 80 kb)

Supplementary information S3 (box)

Table 1 abbreviations (PDF 80 kb)

Glossary

Respiratory chain enzyme complexes

A set of four enzyme complexes that couple the transfer of electrons from carrier molecules, such as NADH or FADH2, to a series of electron acceptors of increasing affinity and, ultimately, to molecular oxygen, which is coupled to the pumping of protons across the inner mitochondrial membrane to generate an electrochemical potential.

ATP synthase

Rotary enzyme in the inner mitochondrial membrane that couples the proton motive force to the synthesis of ATP.

Oxidative phosphorylation

The process of coupling oxidation of nutrients and electron transfer to molecular oxygen with the proton motive force for ATP synthesis.

Reducing equivalents

The major electron acceptors NAD+ and FAD, which are used in the breakdown of the carbon backbone of nutrients to produce the reduced molecules NADH and FADH2.

Electrochemical potential

The [H+] gradient across the inner mitochondrial membrane that is generated through proton pumping by the respiratory chain complexes.

Lactic acidosis

Elevation of lactate, which is a product of glycolytic energy metabolism, in the blood of patients, resulting in life-threatening acidification.

Cofactors

Molecules required for the function of enzymes and/or the progression of metabolic pathways.

Alphaproteobacteria

A class of Gram-negative bacteria, including intracellular parasites, from which mitochondria are thought to have originated following an endosymbiotic event that gave rise to eukaryotes.

Replisome

Enzymes and proteins that function at DNA replication forks.

Progeric syndrome

A group of genetic disorders that manifest with symptoms of premature ageing.

Shine–Dalgarno sequence

A ribosome binding site that is located upstream of the AUG start codon.

Aminoacyl-tRNA synthetases

Enzymes that catalyse the charging of individual tRNAs with their cognate amino acid.

Ribosomal release factors

Release factors terminate translation elongation by catalysing cleavage of the ester bond of the polypeptidyl-tRNA to release the nascent chain from the ribosome.

Polycistronic

A product of transcription that generates RNA molecules that encode more than one protein.

MELAS

(Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes). A mitochondrial disease that is most commonly caused by a mutation (m.3243A>G) in the mitochondrial DNA-encoded tRNALeu(UUR).

MERRF

(Myoclonic epilepsy with ragged red fibres). A mitochondrial disease with variable symptoms, which affects predominantly the nervous system and the muscles.

One-carbon cycle

The major biosynthetic pathway of the cell, which is involved in the transfer of nutrient-derived one-carbon groups by one-carbon carriers, such as tetrahydrofolate, to feed methylation reactions and biosynthesis reactions, such as purine, phospholipid, creatine, amino acid and glutathione synthesis.

Paracrine

A form of cell-to-cell communication, in which a secreted factor affects the function of nearby cells.

Endocrine

A form of cell-to-cell communication, in which a secreted factor (for example, a hormone or cytokine) enters the bloodstream and affects the functions of distant cells or whole tissues.

Redox signalling

A process in which reactive oxygen species or other molecules that carry reducing equivalents (such as NADH, NAD+; NADP and NADPH) change protein functions through reduction or oxidation reactions.

Mitochondrial folate cycle

The mitochondrial part of the one-carbon cycle, in which tetrahydrofolate-forms carry one-carbon units to mitochondrial formylation reactions, generates formate for purine synthesis, formyl-methionine for mitochondrial translation as well as NADPH.

Mechanistic target of rapamycin complex 1

(mTORC1). A kinase that is part of the mTOR complex, which is a master regulator of anabolic biosynthesis.

Liver ketogenesis

Hepatic synthesis of ketone bodies, which is typically induced by fasting and provides tissues with fuel in low-nutrient conditions.

β-oxidation

Stepwise catabolic breakdown of the long carbon backbones of fatty acids in mitochondria, to generate fatty acyl-CoA that enters the Krebs cycle and eventually promotes ATP production.

Hypothalamus

A region in the brain that controls several homeostatic functions of the whole body, including feeding, water intake and the sleep–wake cycle.

Sirtuins

A group of NAD+-dependent proteins that couple NAD+ breakdown to the removal of acyl groups from other proteins.

PPARγ co-activator 1α

(PGC1α). A master transcriptional regulator of the expression of genes that are involved in energy metabolism.

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Suomalainen, A., Battersby, B. Mitochondrial diseases: the contribution of organelle stress responses to pathology. Nat Rev Mol Cell Biol 19, 77–92 (2018). https://doi.org/10.1038/nrm.2017.66

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