New insights into the role of mitochondria in aging: mitochondrial dynamics and more

Abstract

A decline in mitochondrial function plays a key role in the aging process and increases the incidence of age-related disorders. A deeper understanding of the intricate nature of mitochondrial dynamics, which is described as the balance between mitochondrial fusion and fission, has revealed that functional and structural alterations in mitochondrial morphology are important factors in several key pathologies associated with aging. Indeed, a recent wave of studies has demonstrated the pleiotropic role of fusion and fission proteins in numerous cellular processes, including mitochondrial metabolism, redox signaling, the maintenance of mitochondrial DNA and cell death. Additionally, mitochondrial fusion and fission, together with autophagy, have been proposed to form a quality-maintenance mechanism that facilitates the removal of damaged mitochondria from the cell, a process that is particularly important to forestall aging. Thus, dysfunctional regulation of mitochondrial dynamics might be one of the intrinsic causes of mitochondrial dysfunction, which contributes to oxidative stress and cell death during the aging process. In this Commentary, we discuss recent studies that have converged at a consensus regarding the involvement of mitochondrial dynamics in key cellular processes, and introduce a possible link between abnormal mitochondrial dynamics and aging.

Fig. 1.

Proposed model of mitochondrial dysfunction in aging. Toxic ROS generated during normal biological activity gradually impair cellular homeostatic pathways that defend against cellular stress and damage mitochondrial constituents, including the electron transfer chain (ETC) and mtDNA. Oxidative insults to mitochondria, in turn, impair the life-sustaining functions of the organelle – such as energy transduction, biogenesis of metabolites, Ca²⁺ homeostasis and regulation of redox biology – with age, thereby contributing to a vicious cycle of accumulating mitochondrial damage that culminates in a mitochondrial functional crisis. This ultimately results in cell death and aging.

Fig. 2.

Schematic illustration depicting the core proteins of the molecular machinery that mediate mitochondrial fusion and fission in yeast and mammals. (A) Fusion proteins Mfn1 and Mfn2 (mammalian orthologs of yeast Fzo1p) contain four heptad repeats, one GTPase domain and two transmembrane domains. Opa1 (mammalian ortholog of yeast Mgm1p) is another fusion protein, located in the MIM and intermembrane space. The fusion process requires three steps: docking, MOM fusion and MIM fusion. Mfn1 and Mfn2 are thought to play an important role in docking and MOM fusion. Opa1 seems to be involved in the formation of cristae junctions as well as in MIM fusion, which occurs in a GTP-dependent manner. (B) The fission protein Drp1 (mammalian ortholog of yeast Dnm1p) contains one N-terminal GTPase domain, a C-terminal GED (GTPase effector domain) and a hydrophilic region in the middle. Drp1 self-oligomerizes and assembles a scission machine around the MOM. Fis1 (mammalian ortholog of yeast Fis1p) is a MOM protein and is thought to recruit Drp1 to the MOM by means of adaptor proteins.

Fig. 3.

Possible relationship between mitochondrial fusion, fission, biogenesis and degradation. An ongoing mitochondrial fusion–fission cycle allows mitochondrial functional and genetic complementation, and the proper distribution of newly synthesized mitochondria during cell division. However, an imbalance in fusion and fission events – for example, more frequent fission than fusion – might increase the total number of small mitochondria per cell if extra mitochondria are not eliminated by mitophagy. Conversely, more frequent fusion could result in large tubular networks of mitochondria. Mitochondrial biogenesis is required to compensate for decreased mitochondrial biomass resulting from mitochondrial degradation (Berman et al., 2009). Therefore, an imbalance between mitochondrial fusion, fission, biogenesis and degradation events could cause substantial changes in mitochondrial number, biomass, shape and function. P indicates a phagophore by which targeted mitochondria are engulfed during the sequestering process required for mitophagy.

Fig. 4.

Model of the influence of mitochondrial dynamics on aging. Aging compromises the plasticity of mitochondria by disrupting the homeostatic regulation of mitochondrial fusion and fission pathways, resulting in abnormal mitochondrial morphology. The presence of fragmented mitochondria owing to a decline in fusion and/or an increase in fission events can compromise mtDNA integrity, mitochondrial structural and functional complementation, and mitochondrial biogenesis, all of which can lead to mitochondrial dysfunction. Conversely, the formation of enlarged mitochondria as a result of decreased fission and/or increased fusion events can diminish mitochondrial turnover by impairing mitophagy and biogenesis, leading to the accumulation of damaged mitochondria in aged cells. In both cases, the abnormal mitochondria are unable to fulfill their life-sustaining roles. Therefore, age-associated alterations in mitochondrial fusion and fission dynamics might play a causative role in mitochondrial dysfunction, and increase susceptibility to cell death in response to various types of stress during progressive aging.