Structural basis of respiratory complexes adaptation to cold temperatures
Posted on: 10 April 2024
Preprint posted on 17 January 2024
Discover how organisms adapt to cold weather! Shin and Latorre-Muro et al. unveil a mitochondrial response to low temperatures in their comprehensive study of respiration and heat generation.
Selected by Pamela OrnelasCategories: biochemistry, biophysics, cell biology
Background
When exposed to cold environments, mammals activate brown adipocyte cells (BAs) to generate heat and regulate body temperature (1). BAs, dense with mitochondrial cristae, undergo deep protein and lipid remodeling to sustain heightened oxidation rates of glucose and fatty acids in response to low temperatures (2). This adaptation mechanism relies on the electron transport chain (ETC) within mitochondria, which generates a proton motive force that can be used to release energy in the form of heat (3,4). However, the structural basis of cold-induced effects on respiratory complexes is not well understood.
In their preprint, Shin, Latorre-Muro, and colleagues combined thermoregulatory physiology and cryo-electron microscopy (cryoEM) to investigate respiratory supercomplexes exposed to different temperatures. They identified a cold-induced conformation within the CI:III2 supercomplex, elucidating the unique lipid-protein arrangements that stabilize it.
Key findings
Exposure to cold temperatures
Shin, Latorre-Muro, and colleagues compared brown adipose tissue samples from wild-type and model mice exposed to varying temperatures over 8 days. After mitochondrial solubilization, respiratory supercomplexes were purified through size exclusion chromatography, with subsequent activity determination. Peak fractions were analyzed through single particle cryoEM, resulting in high-resolution maps of the CI:III2 supercomplex across different temperatures. This revealed a conformational change of the respiratory complex as a cold adaptation response.
Respiratory complex remodeling
The study resolved two conformations of the CI:III2 supercomplex. Thermoneutral mouse samples presented only a canonical (type 1) conformation, while a structurally different second conformation (type 2) was also observed in samples of cold-acclimated mice. This suggests that in response to cold temperatures, type 1 respiratory complexes transit to the type 2 conformation. The difference between these conformations lies in the 25˚ rearrangement of the CIII2 axis, perpendicular to the CI membrane domain, resulting in an open angle between the longitudinal CI membrane domain and the CIII2 transversal axes.
Lipids play an important role
Given that lipid remodeling in mitochondrial membranes increases ETC activity (5), Shin, Latorre-Muro, and colleagues conducted lipidomics analyses on isolated mitochondria. They found a distinct enrichment in unsaturated phosphatidylethanolamine (PE) and phosphatidylcholine (PC) in tissues exposed to cold and neutral temperatures. Molecular dynamics simulations revealed increased lipid density at the CI/CIII2 interface in the type 2 supercomplex compared to type 1. On this basis, the conformational transition from type 1 to type 2 under cold conditions is proposed to occur by lipid remodeling (PC/PE), increasing membrane flexibility and allowing the accommodation of type 2 complexes to straightened cristae. This results in a lower energy barrier compared to thermoneutral conditions.
In summary, mammalian survival in cold temperatures involves remodeling of brown fat mitochondrial proteins. The authors propose that upon rotation of CIII2, type 2 assemblies become highly active and increase respiration, supporting heat production and maintaining body temperature.
Why is this important?
This preprint provides a great insight into the dynamics of respiratory adaptation under low temperatures. The work presented by Shin, Latorre-Muro, and their colleagues is comprehensive, as they study adipose tissue under different genetic and environmental conditions using cryo-EM, molecular dynamic simulations, and biochemical analyses. This research offers a fresh perspective on cellular temperature regulation and metabolic response to external factors.
I was particularly interested in this work for personal reasons. Every winter, my structural biology friends and I challenge ourselves to swim a nearby lake on Sunday mornings. Our short submersions in near 0˚ C water often prompt discussions about our body’s amazing capacity to adapt to the cold and have sparked our curiosity about metabolism in extreme weather conditions.
Questions to the authors
-
- Do you expect an increase in mitochondrial protein and lipid import under cold-induced stress to make up for the cristae rearrangement? Are there specific regulatory factors involved in this process?
- Based on your molecular dynamics simulations, can you predict the speed of the conformational change between type 1 and 2 assemblies?
- Would you expect similar reorganization in other respiratory supercomplexes to maximize electron transfer?
- Are there shared mechanisms used by prokaryotes to maintain energy production under cold temperatures?
References:
-
- Cannon, J. Nedergaard, Brown adipose tissue: function and physiological significance. Physiol Rev 84, 277–359 (2004).
- Orava, P. Nuutila, M. E. Lidell, V. Oikonen, T. Noponen, T. Viljanen, M. Scheinin, M. Taittonen, T. Niemi, S. Enerbäck, K. A. Virtanen, Different Metabolic Responses of Human Brown Adipose Tissue to Activation by Cold and Insulin. Cell Metab 14, 272–279 (2011).
- Enerbäck, A. Jacobsson, E. M. Simpson, C. Guerra, H. Yamashita, M.-E. Harper, L. P. Kozak, Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature 387, 90–94 (1997).
- Kazak, B. M. Spiegelman, Mechanism of futile creatine cycling in thermogenesis. Am J Physiol Endocrinol Metab 319, E947–E949 (2020).
- G. Sustarsic, T. Ma, M. D. Lynes, M. Larsen, I. Karavaeva, J. F. Havelund, C. H. Nielsen, M. P. Jedrychowski, M. Moreno-Torres, M. Lundh, K. Plucinska, N. Z. Jespersen, T. J. Grevengoed, B. Kramar, J. Peics, J. B. Hansen, F. Shamsi, I. Forss, D. Neess, S. Keipert, J. Wang, K. Stohlmann, I. Brandslund, C. Christensen, M. E. Jørgensen, A. Linneberg, O. Pedersen, M. A. Kiebish, K. Qvortrup, X. Han, B. K. Pedersen, M. Jastroch, S. Mandrup, A. Kjær, S. P. Gygi, T. Hansen, M. P. Gillum, N. Grarup, B. Emanuelli, S. Nielsen, C. Scheele, Y. H. Tseng, N. J. Færgeman, Z. Gerhart-Hines, Cardiolipin Synthesis in Brown and Beige Fat Mitochondria Is Essential for Systemic Energy Homeostasis. Cell Metab 28, 159-174.e11 (2018).
doi: https://doi.org/10.1242/prelights.37071
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