Balancing mitochondrial biogenesis and mitophagy to maintain energy metabolism homeostasis

Abstract

Mitochondria, the main energy hub of the cell, are highly dynamic organelles, playing essential roles in fundamental cellular processes. Mitochondrial function impinges on several signalling pathways modulating cellular metabolism, cell survival and healthspan. Accordingly, impairment of mitochondria has been associated with numerous pathological conditions and ageing. Maintenance of cellular and organismal homeostasis thus hinges on fine-tuning mitochondrial quality control. Mitochondrial biogenesis and mitochondrial selective autophagy (mitophagy), two opposing cellular pathways, coordinately regulate mitochondrial content to sustain energy metabolism, in response to cellular metabolic state, stress and other intracellular or environmental signals. It is not surprising, therefore, that disequilibrium or imbalance between mitochondrial proliferation and degradation processes underlies the onset and progressive unfolding of several pathological conditions in humans, including neurodegenerative diseases, myopathies and other age-associated disorders.Mitochondrial biogenesis is a complex and multistep cellular process, which involves mtDNA transcription and translation, translation of transcripts derived from nucleus, recruitment of newly synthesized proteins and lipids, import and assembly of mitochondrial and nuclear products in the expanding mitochondrial network. Spatiotemporal control of mitochondrial biogenesis is mediated by numerous transcription factors in response to diverse stimuli, including both intracellular signals and environmental stimuli (nutrient availability, growth factors and hormones, toxins, temperature and oxygen fluctuations, among others). The master regulator of mitochondrial energy metabolism is the peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α), the best-studied member of the peroxisome proliferator activated receptor family of transcription co-activators, which orchestrates the activity of several transcription factors involved in mitochondrial biogenesis and function. 1 These include the nuclear respiratory factors (NRF1 and NRF2), the estrogen-related receptors (ERR-α, -β and -γ) and the nuclear factor erythroid 2-related factor 2 (NRF2/NFE2L2) that are part of a complex transcriptional network that regulates mitochondrial biogenesis and energy metabolism. 1,2 Alongside their essential roles in cell and animal physiology, mitochondria are also the major source of potentially hazardous reactive oxygen species as by-products of respiration. Thus, eukaryotic cells have evolved a wide arsenal of quality control mechanisms to preserve mitochondrial homeostasis and prevent cellular damage and eventual death. Mitophagy, a selective type of autophagy, is triggered upon accumulation of damaged or superfluous mitochondria. Dysfunctional mitochondria are targeted and engulfed by double-membrane vesicles known as autophagosomes and are transferred for degradation in lysosomes. Cells induce mitophagy to regulate the size and quality of their mitochondrial network...

The RNA-Binding Protein PUM2 Impairs Mitochondrial Dynamics and Mitophagy During Aging

“…On the other hand, in older worms (day 8), puf-8 depletion increased both mitochondrial mass ( Figure 5F and 5Gs) and mitochondrial DNA content ( Figure 5H), an effect lost in puf-8/dct-1 RNAi nematodes. This is consistent with previous literature showing that long-term boosting of mitophagy is followed by activation of mitochondrial biogenesis (Palikaras et al, 2015;Ryu et al, 2016). These data are also in agreement with the increased citrate synthase activity of old worms exposed to puf-8 RNAi, an effect that is reduced in puf-8/dct-1 worms ( Figure S6E).…”

“…To validate the effect of puf-8 on mitophagy we quantified the mitochondrial mass of muscles of young and old p myo-3 :: mito::GFP worms, as previously described (Palikaras et al, 2015). puf-8 RNAi alone reduced the intensity of the mitochondrial-localized GFP ( Figure 5C and 5Ds), with no differences between puf-8 and puf-8/dct-1 worms, and decreased the mtDNA:nDNA ratio ( Figure 5E) of young adult worms (day 5) in a dct-1-dependent manner.…”

Insulin-like growth factor 1 signaling is essential for mitochondrial biogenesis and mitophagy in cancer cells

“…Similarly, AMPK regulates mitochondrial biogenesis through activation of PGC-1␣ (43), whereas loss of AMPK, and thus its downstream target ULK1, impairs mitophagy during starvation (44). SKN-1, the Caenorhabditis elegans NFE2L2/NRF-2 homologue, drives the expression of various mitochondrial genes but also modulates the expression of DCT-1, the C. elegans homologue of BNIP3 (45). Finally, increased OXPHOS has been shown to promote turnover of mitochondria via Rheb and BNIP3L-mediated mitophagy to maintain optimal efficiency of mitochondrial ATP production (46).…”

Mitochondrial survivin reduces oxidative phosphorylation in cancer cells by inhibiting mitophagy

“…The opposing pathways of mitochondrial biogenesis and autophagic degradation control their quantity and quality. Combined with fusion and fission, these mechanisms govern mitochondrial activity (Palikaras, Lionaki and Tavernarakis, 2015), and alterations to any one of these processes have been linked to ageing and disease (Redmann et al, 2014). In cancer cells these processes are often deregulated, consequently mitochondrial health is compromised: mtDNA harbouring mutations accumulate, respiratory efficiency declines, and ultimately cells switch from OXPHOS to glycolytic dependence (Merz and Westermann, 2009) (Sumpter et al, 2016).…”