Fatty acid oxidation: a neglected factor in understanding the adjustment of mitochondrial function to cold temperatures.

For ectothermic species, adaptation to thermal changes is of critical importance. Mitochondrial oxidative phosphorylation (OXPHOS), which leverages multiple electron pathways to produce energy needed for survival, is among the crucial metabolic processes impacted by temperature. Our aim in this study was to identify how changes in temperature affect the less-studied electron transferring flavoprotein pathway, fed by fatty acid substrates. We used the planarian Dugesia tigrina, acclimated for 4 weeks at 10°C (cold acclimated) or 20°C (normothermic). Respirometry experiments were conducted at an assay temperature of either 10 or 20°C to study specific states of the OXPHOS process using the fatty acid substrates palmitoylcarnitine (long chain), octanoylcarnitine (medium chain) or acetylcarnitine (short chain). Following cold acclimation, octanoylcarnitine exhibited increases in both the OXPHOS and electron transfer (ET, non-coupled) states, indicating that the pathway involved in medium-chain length fatty acids adjusts to cold temperatures. Acetylcarnitine only showed an increase in the OXPHOS state as a result of cold acclimation, but not in the ET state, indicative of a change in phosphorylation system capacity rather than fatty acid ß-oxidation. Palmitoylcarnitine oxidation was unaffected. Our results show that cold acclimation in D. tigrina caused a specific adjustment in the capacity to metabolize medium-chain fatty acids rather than an adjustment in the activity of the enzymes carnitine-acylcarnitine translocase, carnitine acyltransferase and carnitine palmitoyltransferase-2. Here, we provide novel evidence of the alterations in fatty acid ß-oxidation during cold acclimation in D. tigrina.

Selection for late reproduction leads to loss of complex I mitochondrial capacity and associated increased longevity in seed beetles.

Mitochondria play a key role in aging. Here, we measured integrated mitochondrial functions in experimentally evolved lines of the seed beetle Acanthoscelides obtectus that were selected for early (E) or late (L) reproduction for nearly four decades. The two lines have markedly different lifespans (8 days and 13 days in the E and L lines, respectively). The contribution of the NADH pathway to maximal flux was lower in the L compared to the E beetles at young stages, associated to increased control by complex I. In contrast, the contribution of the Succinate pathway was higher in the L than in the E line, while the Proline pathway showed no differences between the lines. Our data suggest that selection of age at reproduction leads to a modulation of complex I activity in mitochondria and that mitochondria are a functional link between evolutionary and mechanistic theories of aging.

The endoplasmic reticulum kinase PERK interacts with the oxidoreductase ERO1 to metabolically adapt mitochondria.

Endoplasmic reticulum (ER) homeostasis requires molecular regulators that tailor mitochondrial bioenergetics to the needs of protein folding. For instance, calnexin maintains mitochondria metabolism and mitochondria-ER contacts (MERCs) through reactive oxygen species (ROS) from NADPH oxidase 4 (NOX4). However, induction of ER stress requires a quick molecular rewiring of mitochondria to adapt to new energy needs. This machinery is not characterized. We now show that the oxidoreductase ERO1⍺ covalently interacts with protein kinase RNA-like ER kinase (PERK) upon treatment with tunicamycin. The PERK-ERO1⍺ interaction requires the C-terminal active site of ERO1⍺ and cysteine 216 of PERK. Moreover, we show that the PERK-ERO1⍺ complex promotes oxidization of MERC proteins and controls mitochondrial dynamics. Using proteinaceous probes, we determined that these functions improve ER-mitochondria Ca2+ flux to maintain bioenergetics in both organelles, while limiting oxidative stress. Therefore, the PERK-ERO1⍺ complex is a key molecular machinery that allows quick metabolic adaptation to ER stress.

Differences in relative capacities of oxidative phosphorylation pathways may explain sex- and tissue-specific susceptibility to vision defects due to mitochondrial dysfunction.

Mitochondrial dysfunction is a major cause and/or contributor to the development and progression of vision defects in many ophthalmologic and mitochondrial diseases. Despite their mechanistic commonality, these diseases exhibit an impressive variety in sex- and tissue-specific penetrance, incidence, and severity. Currently, there is no functional explanation for these differences. We measured the function, relative capacities, and patterns of control of various oxidative phosphorylation pathways in the retina, the eyecup, the extraocular muscles, the optic nerve, and the sciatic nerve of adult male and female rats. We show that the control of mitochondrial respiratory pathways in the visual system is sex- and tissue-specific and that this may be an important factor in determining susceptibility to mitochondrial dysfunction between these groups. The optic nerve showed a low relative capacity of the NADH pathway, depending on complex I, compared to other tissues relying mainly on mitochondria for energy production. Furthermore, NADH pathway capacity is higher in females compared to males, and this sexual dimorphism occurs only in the optic nerve. Our results propose an explanation for Leber's hereditary optic neuropathy, a mitochondrial disease more prevalent in males where the principal tissue affected is the optic nerve. To our knowledge, this is the first study to identify and provide functional explanations for differences in the occurrence and severity of visual defects between tissues and between sexes. Our results highlight the importance of considering sex- and tissue-specific mitochondrial function in elucidating pathophysiological mechanisms of visual defects.