Control of mitochondrial integrity in ageing and disease

Abstract

Various molecular and cellular pathways are active in eukaryotes to control the quality and integrity of mitochondria. These pathways are involved in keeping a 'healthy' population of this essential organelle during the lifetime of the organism. Quality control (QC) systems counteract processes that lead to organellar dysfunction manifesting as degenerative diseases and ageing. We discuss disease- and ageing-related pathways involved in mitochondrial QC: mtDNA repair and reorganization, regeneration of oxidized amino acids, refolding and degradation of severely damaged proteins, degradation of whole mitochondria by mitophagy and finally programmed cell death. The control of the integrity of mtDNA and regulation of its expression is essential to remodel single proteins as well as mitochondrial complexes that determine mitochondrial functions. The redundancy of components, such as proteases, and the hierarchies of the QC raise questions about crosstalk between systems and their precise regulation. The understanding of the underlying mechanisms on the genomic, proteomic, organellar and cellular levels holds the key for the development of interventions for mitochondrial dysfunctions, degenerative processes, ageing and age-related diseases resulting from impairments of mitochondria.

Keywords: ageing; disease; mitochondria; quality control.

Figure 1.

The influence of clonal expansion on mitochondrial integrity with time. Mutations can be introduced de novo or inherited in a number of mtDNA copies (heteroplasmic). Circles inside the mitochondrion are a representation of the mtDNA population for that particular mitochondrion. Normal mtDNA molecules are indicated with solid lines and mtDNA molecules with clonally expanded mutations are depicted with dashed lines. The clonal expansion of mutated mtDNA molecules dominates the expansion of normal mtDNA, indicated by thickness of the downward arrows. The mechanisms of mtDNA repair, selective/non-selective degradation of mtDNA and upregulated mtDNA replication to block clonal expansion at each level of mitochondrial integrity are indicated on the right.

Figure 2.

Interactions between quality control levels in mitochondria. Five QC levels are represented by grey ovals corresponding to mtDNA integrity, proteostasis, dynamics, mitophagy and apoptosis. Proteins (rectangles) and processes (rounded corners) that interact between levels of QC hierarchy are shown. Arrows indicate their influence on other components of QC as described in the text.