Mitochondrial quality control pathways as determinants of metabolic health

Abstract

Mitochondrial function is key for maintaining cellular health, while mitochondrial failure is associated with various pathologies, including inherited metabolic disorders and age-related diseases. In order to maintain mitochondrial quality, several pathways of mitochondrial quality control have evolved. These systems monitor mitochondrial integrity through antioxidants, DNA repair systems, and chaperones and proteases involved in the mitochondrial unfolded protein response. Additional regulation of mitochondrial function involves dynamic exchange of components through mitochondrial fusion and fission. Sustained stress induces a selective autophagy - termed mitophagy - and ultimately leads to apoptosis. Together, these systems form a network that acts on the molecular, organellar, and cellular level. In this review, we highlight how these systems are regulated in an integrated context- and time-dependent network of mitochondrial quality control that is implicated in healthy aging.

Keywords: ROS; fission; fusion; mitochondrial dynamics; mitochondrial quality control; mitohormesis; mitophagy.

Figure 1

UPR^mt signal transduction pathway in mammals and worms. Upon mitochondrial proteotoxic stress, CLPP‐1 activity is required to induce UPR^mt. In C. elegans, peptides processed by CLPP‐1 are exported into the cytosol by the transporter protein HAF‐1 and attenuate mitochondrial protein import. Consequently, the transcription factor ATFS‐1, which would normally be degraded in the matrix by Lon protease, accumulates in the cytosol. Upon accumulation, ATFS‐1 translocates to the nucleus together with DVE‐1 and UBL‐5 to activate UPR^mt responsive genes. Protein translation can be attenuated in a complementary pathway that depends on ROS signaling. In mammals, it is not completely clear how the signal is propagated to the nucleus. ClpP activity is also required for mammalian UPR^mt induction, although the putative transporter protein (HAF‐1 ortholog) is yet to be identified. Furthermore, it involves attenuation of mitochondrial import through YME1L1‐mediated degradation of TIM23 component (TIM17A). Activation of JNK2 kinase and subsequent activation of transcription factor c‐Jun induces expression of CHOP and C/EBPß leading to the induction of UPR^mt responsive genes. PKR inhibits translation through the phosphorylating eIF2α, and is also involved in c‐Jun activation. The UPR^mt signaling components confirmed in worms are depicted in gray, the mammalian confirmed signaling components in blue, and proteins confirmed in both are shown in purple.

Figure 2

Mitochondrial life cycle. Mitochondria are continuously alternating between fusion and fission events. Fission allows segregation of damaged mitochondria that may be transiently depolarized. After separation, mitochondria are degraded by mitophagy if the depolarization sustains or if the mitochondrion is terminally damaged. The other daughter mitochondrion can continue to cycle between fusion and fission events.

Figure 3

Mitochondrial quality control pathway interaction. Depending on the type of stress stimuli a corresponding mitochondrial stress response is induced. For instance, in case of oxidative stress antioxidants and DNA repair enzymes are activated. Simultaneously, mitochondrial chaperones and proteases may be upregulated via the mitochondrial unfolded response (UPR^mt). Damaged components can be diluted in the mitochondrial network through fusion, whereas severely damaged mitochondria are separated from the network by fission and subsequently degraded by mitophagy. In contrast to the classical hierarchical view of sequential mitochondrial quality control activation, we postulate that this activation is highly context‐ and time‐dependent. The dashed arrows indicate that the period and level of stress activation lead to crosstalk between the different stress responses, which depend on the type of stress stimulus and its duration. Prolonged stress or severe damage not only elicits mitochondrial repair responses, but ultimately leads to apoptosis.