Mitophagy controls beige adipocyte maintenance through a Parkin-dependent and UCP1-independent mechanism

Abstract

Beige adipocytes are an inducible form of mitochondria-enriched thermogenic adipocytes that emerge in response to external stimuli, such as chronic cold exposure. We have previously shown that after the withdrawal of external stimuli, beige adipocytes directly acquire a white fat-like phenotype through autophagy-mediated mitochondrial degradation. We investigated the upstream pathway that mediates mitochondrial clearance and report that Parkin-mediated mitophagy plays a key role in the beige-to-white adipocyte transition. Mice genetically deficient in showed reduced mitochondrial degradation and retained thermogenic beige adipocytes even after the withdrawal of external stimuli. Norepinephrine signaling through the PKA pathway inhibited the recruitment of Parkin protein to mitochondria in beige adipocytes. However, mitochondrial proton uncoupling by uncoupling protein 1 (UCP1) was dispensable for Parkin recruitment and beige adipocyte maintenance. These results suggest a physiological mechanism by which external cues control mitochondrial homeostasis in thermogenic fat cells through mitophagy.

Breast milk alkylglycerols sustain beige adipocytes through adipose tissue macrophages

“…AKG treatment also reduced the amount of crown-like structures ( Figure 6I), which are sites of inflammatory ATM activation (60-62). Indirect calorimetry indicated that AKGs decreased the respiratory ing mitophagy (65). Accordingly, NPFF-treated 3T3-L1 adipocytes contained a greater number of mitophagosomes than vehicle-treated adipocytes ( Figure 7E).…”

“…BeAT development is associated with increased mitochondrial content and uncoupling, which can have unfavorable outcomes when it occurs in excess (63,64). The expansion of the mitochondrial network is thus maintained in a physiological range by signals that remain the subject of intense research (65,66). It is intriguing that AKGs had an effect only in neonates and in adult obese mice and were ineffective in lean adult mice.…”

“…The adipocyte effect of NPFF was due to its binding to NPFFR1, which was expressed by 3T3-L1 adipocytes (Supplemental Figure 15I). Autophagy allows metabolic adaptation (72), and it coordinates with mitochondrial biogenesis to maintain healthy metabolism (65,66,73).…”

Parkin controls brown adipose tissue plasticity in response to adaptive thermogenesis

“…In chronic CL316,243 treatment and withdrawal experiments, mice were maintained at thermoneutral (29°C) temperature, as in Ref. Tissues were dissected, weighed, and frozen for further mRNA and protein analyses, or they were fixed and processed for microscopic analyses (see below).…”

Assessment of mitophagy in mt‐Keima Drosophila revealed an essential role of the PINK1‐Parkin pathway in mitophagy induction in vivo

“…In addition, the resistance of mt-Keima to lysosomal degradation causes the integration of the mt-Keima signal, allowing for the easy quantitative measurement of mitophagy activity. These properties have led to the increasing use of mt-Keima to study mitophagy in vitro (13)(14)(15)(16). We previously generated a transgenic mouse that ubiquitously expresses the mt-Keima protein, allowing the first general observation of in vivo mitophagy (17).…”