Mitochondrial Bioenergetics in Physiology

Physiology aims to understand the mechanisms that enable organisms to live in and adapt to their environment. These mechanisms range from the whole organism to the molecular level, but in all cases, energy has to be funneled into specific cellular functions. The central interfaces converting nutrients to cellular energy are small intracellular organelles, the mitochondria. Given the pivotal role of mitochondrial bioenergetics for powering physiology, a very active research field currently seeks to decipher how mitochondrial functions are integrated into cellular and organismic physiology, and how mitochondria contribute to ecological adaptation and human diseases.

Acta Physiologica recently collated a special issue titled ‘Mitochondrial Bioenergetics in Physiology’, covering various aspects of mitochondrial adaptations in ectotherms, heat production in endotherms, the role of mitochondria in metabolic signaling during physiological challenges, and the function of mitochondrial transporters (Figure 1). The special issue reports on various aspects of mitochondrial involvement in health and disease, such as sarcopenia, pulmonary hypertension and cardioprotection, and factors regulating mitochondrial function, including microRNA and mitophagy, expanding our current understanding on mitochondrial physiology.

Despite their many cellular functions, mitochondria are best known for the oxidation of substrates to transport electrons along the respiratory chain, using the liberated energy to pump protons from the matrix over the mitochondrial inner membrane into the intermembrane space, thereby storing potential energy in a proton gradient that produces ATP. Although this mechanism is universal to all mitochondria, the efficiency and regulation differ tremendously between organisms, organs, and cell types, as they have to deal with different environmental and physiological challenges, requiring molecular integration into specific cellular functions to match energetic supply and demand.

The thermal environment of mitochondria can vary greatly in ectothermic organisms, where body temperature tracks the ambient temperature. Ectotherms represent beautiful model organisms to understand the effects of temperature on mitochondrial function and its relation to adaptation and physiological performance [1]. The Crucian carp, for example, lives in Scandinavian lakes and experiences frequent fluctuations in temperature and oxygenation that require different handling of mitochondrial oxidative stress as compared to mitochondria of the mouse [2]. Exposing fish to different temperatures over multiple generations uncovers that mitochondrial efficiency can adapt [3].

Mitochondria of endothermic birds and mammals are surrounded by a mostly warm environment, created by heat production of mitochondria themselves. We are still not sure how sufficient mitochondrial capacity evolved to sustain endothermy, but some reptiles, such as tegu lizards, are capable of facultative heat production for offspring incubation and reproduction [4]. New data suggest that these endothermic episodes are accompanied by mitochondrial adaptation in skeletal muscle [5], casting light on the molecular source of heat and drawing a picture of events that progressed towards sustained endothermy.

How mitochondria can ramp up heat production in endotherms is well described for brown adipose tissue (BAT), a heater organ that evolved rather late in mammalian evolution, only in eutherian mammals [6]. Brown adipocytes are filled with mitochondria and express a specific thermogenic protein, called uncoupling protein 1 (UCP1), residing in the mitochondrial inner membrane. UCP1 bypasses the ATP synthase by leaking protons back into the mitochondrial matrix, thereby not only dissipating the stored energy of the electrochemical gradient as heat, but also unleashing high oxidation rates that are uncoupled from cellular ATP homeostasis. About 50 years ago, the Nicholls laboratory made a quantum leap towards the understanding of BAT thermogenesis, reviewed from an authentic viewpoint [7]. Despite recently published cryo-EM structures [8, 9], the molecular mechanism of proton translocation is still not resolved, maintaining an active research field to understand the regulation of UCP1.

Musiol and colleagues discovered differences in the inhibitor sensitivity between mouse and human variants, suggesting that naturally occurring functional differences are encoded at the protein level [10]. Other members of the mitochondrial solute carrier family 25 (SLC25) can also leak protons, such as the 2-oxoglutarate/malate carrier [11]. Dissipating the proton gradient to increase metabolic rates has been of interest for the biomedical community for a long time, promoting the synthesis of chemical uncoupling agents. A new study shows that the uncoupler BAM15 improves metabolic profiles in preclinical models of fatty liver disease [12].

The canonical function of SLC25 and other transporters, however, is the exchange of biomolecules between the cytosol and the mitochondrion, and while interfering can cause dysfunction and disease, the transporters also represent drug target opportunities for a variety of diseases (reviewed by [13]). For precision drug design, protein structures and transport mechanisms need to be revealed. Tavoulari and colleagues review the history and challenges surrounding the transport of the glycolytic end product pyruvate into the mitochondrial matrix [14], which just recently culminated in the resolution of both the mechanism and structure [15-17].

The involvement of mitochondrial biology in disease is diverse and, despite major progress, many aspects are still at the discovery stage. Mitochondria are involved in metabolic diseases, brain function, aging, and many other processes. In this issue, we learn how mitochondria maintain organ function via protein quality control, can be a foe during oxidative stress, control systemic metabolism, and get a glance at novel ways of regulating mitochondrial function, for example, via microRNAs.

Disturbed mitochondrial quality control can lead to a variety of diseases. Thus, it is important to clear dysfunctional mitochondria in a process called mitophagy. A new study shows that the transcription factor HIF-1α seems to mediate cardioprotection during myocardial infarction by promoting mitophagy [18]. Mitochondrial quality control can be impacted by ingested chemicals such as caffeine, which appears to act via parkin, a critical protein involved in mitophagy, in the regenerating muscle [19]. Most mitochondrial proteins are nuclear-encoded and need to be imported to mitochondria. Vazquez-Calvo and colleagues investigate the sensitivity of newly imported proteins to aggregation, highlighting the role of protein quality control (PQC) systems in maintaining mitochondrial function [20].

Mitochondrial reactive oxygen species (ROS) production can cause damage, particularly during ischemia–reperfusion when organs are exposed to variable concentrations of oxygen and substrates. We still do not have a complete understanding of which mechanisms increase or counteract fluctuating ROS levels. Li and colleagues suggest that mitochondrial fumarate can promote tubular injury following ischemia/reperfusion injury (I/RI) in renal cells [21]. Compound Z, a large-conductance Ca²⁺−activated K⁺ channel (BKCa) activator, can prevent mitochondrial dysfunction caused by oxygen deprivation, highlighting its ability to reduce ROS production during hypoxia/reoxygenation [22]. The emerging field of microRNAs interfaces with mitochondrial function, showing that miRNA210 seems to be involved in the pathophysiology of mitochondria during hypoxia-induced pulmonary hypertension [23].

Mitochondrial function differs tremendously between different organs and cell types. Pancreatic beta cells provide a unique mitochondrial setup by translating glucose sensing into increased ATP/ADP ratios, subsequently triggering insulin secretion. Munoz and colleagues review how this unique metabolic setup is disturbed during the sequelae of type 2 diabetes [24], while others show how miR-29 can influence mitochondrial function [25].

In many other cell types, mitochondrial respiration is controlled by ATP demand. If mitochondria are unable to match ATP demand, cellular and organ functions will inevitably decline, as seen in aging processes. Comparing mitochondrial respiration in the hippocampus of differently aging guinea pig strains highlights the link between mitochondrial performance, aging, and cognitive decline [26]. Muscle mitochondria must provide ATP for movement and strength. Sarcopenia, the progressive loss of muscle mass and function impacting life quality and health, is raising a lot of interest for targeting mitochondria to counteract muscle atrophy [27]. Physical activity is currently the only known treatment for sarcopenia, and a single bout of exercise appears to initiate events related to mitophagy [28]. Others find that endurance training enhances the interaction between myoglobin and respiratory complex IV [29]. In the complex regulatory network of the muscle, the mitogen-activated protein kinases (MAPK) p38 alpha, within the family of serine/threonine kinases, was identified as a critical mediator of mitochondrial function [30]. Furthermore, overexpressing Mitofusin 2 (Mfn2), which controls mitochondrial fusion events in mouse muscle, improves muscle mass and mitochondrial function, counteracting sarcopenia [31]. Mitochondria also buffer calcium levels for various muscle functions, as shown in a study ablating parvalbumin, the primary calcium buffer in muscle [32].

This special issue on mitochondria is evidence that the research community is increasingly acknowledging the bioenergetic role of mitochondria in physiology, identifying new facets of regulation and mechanisms, sparking new research to unravel the mechanistic links between mitochondria and physiology.

The authors declare no conflicts of interest.