Mitochondrial quality control: Easy come, easy go

Abstract

"Friends come and go but enemies accumulate." - Arthur Bloch Mitochondrial networks in eukaryotic cells are maintained via regular cycles of degradation and biogenesis. These complex processes function in concert with one another to eliminate dysfunctional mitochondria in a specific and targeted manner and coordinate the biogenesis of new organelles. This review covers the two aspects of mitochondrial turnover, focusing on the main pathways and mechanisms involved. The review also summarizes the current methods and techniques for analyzing mitochondrial turnover in vivo and in vitro, from the whole animal proteome level to the level of single organelle.

Keywords: Autophagy; Cardiac; Mitochondria; Mitochondrial biogenesis; Mitophagy.

Figure 1. Overview of Mitophagy

Inactivation of mitochondria-resident proteases in depolarized mitochondria leads to an accumulation of PINK1 on the outer mitochondrial membrane. The phosphorylation of outer membrane proteins such as Mfn1/2 leads to their ubiquitination by Parkin. The fission machinery separates the dysfunctional mitochondrion from the network, and the ubiquitinated proteins serve as binding sites for autophagy adaptor proteins such as p62. These proteins contain LC3 binding sites, leading to encapsulation of the organelle in an autophagic vesicle, which is delivered to the lysosome for degradation.

Figure 2. Overview of Mitochondrial Biogenesis

The bulk of biogenesis is controlled by the transcription factor PGC-1α. External stimuli such as cold, exercise or nutritional deprivation activate signaling cascades which lead to activation of PGC-1α. PGC-1α activates the transcription of other transcription factors such as NRF1, which are responsible for driving the transcription of nuclear-encoded mitochondrial proteins.

Figure 3. MitoTimer

(A) C2C12 cells expressing Tet-inducible MitoTimer, exposed to Dox for 1 h, and then imaged at 4, 8, 12, 24, 48 and 72 h. Merged images of green and red channels are shown; smaller insets show the expression levels of MitoTimer green and MitoTimer red fluorescence. (B) Heterogeneous expression of MitoTimer fluorescence, indicating mitochondria with differential rates of import.

Figure 3. MitoTimer

(A) C2C12 cells expressing Tet-inducible MitoTimer, exposed to Dox for 1 h, and then imaged at 4, 8, 12, 24, 48 and 72 h. Merged images of green and red channels are shown; smaller insets show the expression levels of MitoTimer green and MitoTimer red fluorescence. (B) Heterogeneous expression of MitoTimer fluorescence, indicating mitochondria with differential rates of import.