bims-mimbat 2023-01-01 papers

Am J Physiol Regul Integr Comp Physiol. 2022 Dec 26.

How does density of the inner mitochondrial membrane influence mitochondrial performance?

Kyle B Heine, Hailey A Parry, Wendy R Hood.

Our current understanding of variation in mitochondrial performance is incomplete. The production of ATP via oxidative phosphorylation is dependent, in part, upon the structure of the inner mitochondrial membrane. Morphology of the inner membrane is crucial for the formation of the proton gradient across the inner membrane and, therefore, ATP synthesis. The inner mitochondrial membrane is dynamic, changing shape and surface area. These changes alter density (amount per volume) of the inner mitochondrial membrane within the confined space of the mitochondrion. Because the number of electron transport system proteins within the inner mitochondrial membrane changes with inner mitochondrial membrane area, a change in the amount of inner membrane alters the capacity for ATP production within the organelle. This review outlines the evidence that the association between ATP synthases, inner mitochondrial membrane density, and mitochondrial density (number of mitochondria per cell), impact ATP production by mitochondria. Further, we consider possible constraints on the capacity of mitochondria to produce ATP by increasing inner mitochondrial membrane density.

Keywords: ATP synthase; cristae; inter-membrane space; matrix; oxidative phosphorylation

DOI: https://doi.org/10.1152/ajpregu.00254.2022

Cell Rep. 2022 Dec 27. pii: S2211-1247(22)01793-4. [Epub ahead of print]41(13): 111894

UCP2-dependent redox sensing in POMC neurons regulates feeding.

Nal Ae Yoon, Sungho Jin, Jung Dae Kim, Zhong Wu Liu, Qiushi Sun, Rebecca Cardone, Richard Kibbey, Sabrina Diano.

Paradoxically, glucose, the primary driver of satiety, activates a small population of anorexigenic pro-opiomelanocortin (POMC) neurons. Here, we show that lactate levels in the circulation and in the cerebrospinal fluid are elevated in the fed state and the addition of lactate to glucose activates the majority of POMC neurons while increasing cytosolic NADH generation, mitochondrial respiration, and extracellular pyruvate levels. Inhibition of lactate dehydrogenases diminishes mitochondrial respiration, NADH production, and POMC neuronal activity. However, inhibition of the mitochondrial pyruvate carrier has no effect. POMC-specific downregulation of Ucp2 (Ucp2PomcKO), a molecule regulated by fatty acid metabolism and shown to play a role as transporter in the malate-aspartate shuttle, abolishes lactate- and glucose-sensing of POMC neurons. Ucp2PomcKO mice have impaired glucose metabolism and are prone to obesity on a high-fat diet. Altogether, our data show that lactate through redox signaling and blocking mitochondrial glucose utilization activates POMC neurons to regulate feeding and glucose metabolism.

Keywords: CP: Metabolism; CP: Neuroscience; NADH; UCP2; feeding behavior; glucose; hypothalamus; lactate; lipid utilization; mitochondria; pro-opiomelanocortin neurons; redox signaling

DOI: https://doi.org/10.1016/j.celrep.2022.111894

Proc Natl Acad Sci U S A. 2023 Jan 03. 120(1): e2214874120

Lipid kinase PIK3C3 maintains healthy brown and white adipose tissues to prevent metabolic diseases.

Wenqiang Song, J Luke Postoak, Guan Yang, Xingyi Guo, Heather H Pua, Jackie Bader, Jeffrey C Rathmell, Hanako Kobayashi, Volker H Haase, Katrina L Leaptrot, Alexandra C Schrimpe-Rutledge, Stacy D Sherrod, John A McLean, Jianhua Zhang, Lan Wu, Luc Van Kaer.

Adequate mass and function of adipose tissues (ATs) play essential roles in preventing metabolic perturbations. The pathological reduction of ATs in lipodystrophy leads to an array of metabolic diseases. Understanding the underlying mechanisms may benefit the development of effective therapies. Several cellular processes, including autophagy and vesicle trafficking, function collectively to maintain AT homeostasis. Here, we investigated the impact of adipocyte-specific deletion of the lipid kinase phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3) on AT homeostasis and systemic metabolism in mice. We report that PIK3C3 functions in all ATs and that its absence disturbs adipocyte autophagy and hinders adipocyte differentiation, survival, and function with differential effects on brown and white ATs. These abnormalities cause loss of white ATs, whitening followed by loss of brown ATs, and impaired "browning" of white ATs. Consequently, mice exhibit compromised thermogenic capacity and develop dyslipidemia, hepatic steatosis, insulin resistance, and type 2 diabetes. While these effects of PIK3C3 largely contrast previous findings with the autophagy-related (ATG) protein ATG7 in adipocytes, mice with a combined deficiency in both factors reveal a dominant role of the PIK3C3-deficient phenotype. We have also found that dietary lipid excess exacerbates AT pathologies caused by PIK3C3 deficiency. Surprisingly, glucose tolerance is spared in adipocyte-specific PIK3C3-deficient mice, a phenotype that is more evident during dietary lipid excess. These findings reveal a crucial yet complex role for PIK3C3 in ATs, with potential therapeutic implications.

Keywords: PIK3C3/VPS34; adipocyte; autophagy; lipodystrophy; metabolic disease

DOI: https://doi.org/10.1073/pnas.2214874120

Proc Natl Acad Sci U S A. 2023 Jan 03. 120(1): e2213437120

Differential dynamics and direct interaction of bound ligands with lipids in multidrug transporter ABCG2.

Ali Rasouli, Qin Yu, Sepehr Dehghani-Ghahnaviyeh, Po-Chao Wen, Julia Kowal, Kaspar P Locher, Emad Tajkhorshid.

ABCG2 is an ATP-binding cassette (ABC) transporter that extrudes a wide range of xenobiotics and drugs from the cell and contributes to multidrug resistance in cancer cells. Following our recent structural characterization of topotecan-bound ABCG2, here, we present cryo-EM structures of ABCG2 under turnover conditions in complex with a special modulator and slow substrate, tariquidar, in nanodiscs. The structures reveal that similar to topotecan, tariquidar induces two distinct ABCG2 conformations under turnover conditions (turnover-1 and turnover-2). μs-scale molecular dynamics simulations of drug-bound and apo ABCG2 in native-like lipid bilayers, in both topotecan- and tariquidar-bound states, characterize the ligand size as a major determinant of its binding stability. The simulations highlight direct lipid-drug interactions for the smaller topotecan, which exhibits a highly dynamic binding mode. In contrast, the larger tariquidar occupies most of the available volume in the binding pocket, thus leaving little space for lipids to enter the cavity and interact with it. Similarly, when simulating ABCG2 in the apo inward-open state, we also observe spontaneous penetration of phospholipids into the binding cavity. The captured phospholipid diffusion pathway into ABCG2 offers a putative general path to recruit any hydrophobic/amphiphilic substrates directly from the membrane. Our simulations also reveal that ABCG2 rejects cholesterol as a substrate, which is omnipresent in plasma membranes that contain ABCG2. At the same time, cholesterol is found to prohibit the penetration of phospholipids into ABCG2. These molecular findings have direct functional ramifications on ABCG2's function as a transporter.

Keywords: ABC transporters; cryo-EM; lipids; membrane proteins; molecular dynamics

DOI: https://doi.org/10.1073/pnas.2213437120

Biochimie. 2022 Dec 27. pii: S0300-9084(22)00333-9. [Epub ahead of print]

Cold stress during room temperature housing alters skeletal response to simulated microgravity (hindlimb unloading) in growing female C57BL6 mice.

Carmen P Wong, Adam J Branscum, Aidan R Fichter, Jennifer Sargent, Urszula T Iwaniec, Russell T Turner.

Laboratory mice are typically housed at temperatures below the thermoneutral zone for the species, resulting in cold stress and premature cancellous bone loss. Furthermore, mice are more dependent upon non-shivering thermogenesis to maintain body temperature during spaceflight, suggesting that microgravity-induced bone loss may be due, in part, to altered thermogenesis. Consequently, we assessed whether housing mice at room temperature modifies the skeletal response to simulated microgravity. This possibility was tested using the hindlimb unloading (HLU) model to mechanically unload femora. Humeri were also assessed as they remain weight bearing during HLU. Six-week-old female C57BL6 (B6) mice were housed at room temperature (22 °C) or near thermoneutral (32 °C) and HLU for 2 weeks. Compared to baseline, HLU resulted in cortical bone loss in femur, but the magnitude of reduction was greater in mice housed at 22 °C. Cancellous osteopenia in distal femur (metaphysis and epiphysis) was noted in HLU mice housed at both temperatures. However, bone loss occurred at 22 °C, whereas the bone deficit at 32 °C was due to failure to accrue bone. HLU resulted in cortical and cancellous bone deficits (compared to baseline) in humeri of mice housed at 22 °C. In contrast, fewer osteopenic changes were detected in mice housed at 32 °C. These findings support the hypothesis that environmental temperature alters the skeletal response to HLU in growing female mice in a bone compartment-specific manner. Taken together, species differences in thermoregulation should be taken into consideration when interpreting the skeletal response to simulated microgravity.

Keywords: Bone loss; Cold stress; Microgravity; Osteopenia; Weight bearing

DOI: https://doi.org/10.1016/j.biochi.2022.12.009