Mitochondrial quality control: an integrated network of pathways

doi:10.1016/j.tibs.2012.02.004

Trends in Biochemical Sciences

Volume 37, Issue 7, July 2012, Pages 284-292

https://doi.org/10.1016/j.tibs.2012.02.004 Get rights and content

Mitochondria are organelles of eukaryotic cells with various functions. Best known is their role in energy transduction leading to the formation of ATP. As byproducts of this process, reactive oxygen species (ROS) are formed that can damage different types of molecules leading to mitochondrial dysfunction. Different quality control (QC) mechanisms keep mitochondria functional. Although several components involved in mitochondrial QC have been characterized in some detail, others remain to be integrated into what is currently emerging as a hierarchical network of interacting pathways. The elucidation of this network holds the key to the understanding of complex biological processes such as aging and the development of age-related diseases.

Section snippets

Mitochondria: essential and risky

Mitochondria are eukaryotic organelles involved in various functions including, for example, fatty acid metabolism, amino acid and iron/sulfur cluster synthesis, and are best known for the generation of the cellular ‘energy currency’ ATP (Box 1). As byproducts of this process, ROS are formed [1] that can damage various biomolecules. Thus, mitochondria are at the same time essential and potentially dangerous. Different pathways of mitochondrial QC have evolved to counteract the adverse effects

ROS scavenging: a pathway to decelerate the pace of molecular damaging

Superoxide, the primary ROS generated at the respiratory chain (RC), can be converted to hydrogen peroxide (H₂O₂; Box 1). In mitochondria, this process is catalyzed by the nuclear encoded superoxide dismutase isoform, which contains manganese in its active center (MnSod). Although superoxide is not membrane permeable, H₂O₂ can efficiently pass through biomembranes and therefore acts not only at its site of formation but also elsewhere. H₂O₂ can be detoxified by different enzymes, leading to the

Repair and refolding: making damaged cellular components functional again

A second battery of molecular QC pathways act after damage has occurred. These pathways reverse (repair) specific modifications and restore the function of impaired molecules. In particular, the repair of damaged mitochondrial DNA (mtDNA), which encodes a small but essential subset of proteins as well as the two RNA subunits of the mitochondrial ribosome and tRNAs needed for mitochondrial protein biosynthesis, is of great importance. Mitochondria contain efficient DNA repair pathways, including

Removal and replacement: a concerted action to counteract the consequences of irreversible damage

The vast majority of proteins cannot be efficiently repaired or refolded and could exhibit functional alterations following damage by ROS, thereby potentially promoting further decline of cellular function. Hence, irreversibly damaged proteins need to be effectively removed by proteolysis. The importance of this pathway of molecular QC is exemplified by the Cu/Zn superoxide dismutase (Sod1), a ROS scavenging enzyme located in the cytosol and in the mitochondrial intermembrane space (IMS). Sod1

Fission and fusion of mitochondria: content mixing and separation

At the organellar level the fission and fusion of mitochondria is the first pathway of quality control that becomes important when the molecular pathways are overwhelmed. The underlying mechanisms appear to be conserved from yeast to mammals [56]. As they have been most thoroughly studied in yeast, we describe the machinery controlling mitochondrial dynamics from a yeast perspective. Fission of mitochondria is controlled by three proteins. In yeast these are Dnm1, Fis1 and Mdv1. Dnm1 is a

Mitophagy: recycling of compounds

Terminally damaged and dysfunctional mitochondria can be eliminated from the vital mitochondrial network through a process termed mitophagy. Mitophagy represents one type of selective autophagy (‘self-eating’) during which whole mitochondria are engulfed by autophagic membranes and delivered to lysosomes or, in fungi and plants, to vacuoles, leading to the formation of autophagosomes. Within these lytic organelles, mitochondria become degraded and the resulting breakdown products are made

Concluding remarks

The maintenance of mitochondrial function is of key relevance for the integrity of biological systems (Box 2). A variety of QC pathways have evolved to meet this necessity. However, it appears that all pathways of mitochondrial QC are limited in their capacity and eventually become overwhelmed by molecular and/or organellar damage. The successive induction of individual QC pathways, organized in a hierarchical network, emerges as a way to overcome this problem, at least for some time. Some of

Acknowledgments

We wish to thank Mrs B. Tarazi for preparing the artwork. The work of H.D.O. was supported by the Deutsche Forschungsgemeinschaft, the BMBF (GerontoMitoSys), the European Commission (MiMage, Proteomage), Goethe University, and the Cluster of Excellence ‘Macromolecular Complexes’.

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Trends in Biochemical Sciences

ReviewMitochondrial quality control: an integrated network of pathways

Section snippets

Mitochondria: essential and risky

ROS scavenging: a pathway to decelerate the pace of molecular damaging

Repair and refolding: making damaged cellular components functional again

Removal and replacement: a concerted action to counteract the consequences of irreversible damage

Fission and fusion of mitochondria: content mixing and separation

Mitophagy: recycling of compounds

Concluding remarks

Acknowledgments

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EMBO J.

Mitochondrial protein quality control: implications in ageing

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Mitochondrial protein quality control systems in aging and disease

ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis

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Hydrogen peroxide: a Jekyll and Hyde signalling molecule

Cell Death Dis.

The biologic clock: the mitochondria?

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The dual functions of thiol-based peroxidases in H2O2 scavenging and signaling

Antioxid. Redox Signal.

Review
Mitochondrial quality control: an integrated network of pathways

The dual functions of thiol-based peroxidases in H₂O₂ scavenging and signaling