Mitochondrial heterogeneity and adaptations to cellular needs

Abstract

Although it is well described that mitochondria are at the epicentre of the energy demands of a cell, it is becoming important to consider how each cell tailors its mitochondrial composition and functions to suit its particular needs beyond ATP production. Here we provide insight into mitochondrial heterogeneity throughout development as well as in tissues with specific energy demands and discuss how mitochondrial malleability contributes to cell fate determination and tissue remodelling.

Fig. 1 ∣. Changes in mitochondrial metabolism that drive progenitor cell behaviours.

Inducible expression of MitoNEET, which prevents iron entry into mitochondria through MFRN (also known as SLC25A37) and subsequently reduces β-oxidative activity in pre-adipocytes, directs the adipose progenitor lineage to a pro-inflammatory state. An increase in mitochondrial complex I activity, and subsequently ROS production, negatively affects stem cell self-renewal and often results in enhanced cell maturation and differentiation. The addition of chemical uncouplers—such as carbonyl cyanide-p-trifluor omethoxyphenylhydrazone, which dissociates electron transfer from ATP production—results in maturation of HSCs. Loss of complex I assembly factors in the osteogenic progenitor, via inducible complex I assembly factor knockout, renders complex I inactive and subsequently drives a reduction of ATP production, leading to damaged skeletal progenitors. Engagement of non-canonical TCA cycle activity, whereby citrate is exported out of mitochondria to generate cytosolic OAA, underlies the embryonic stem cell exit from pluripotency. Loss of MPCs in intestinal stem cells results in maintenance of the stem cell pool as well as intestinal stem cell proliferation and self-renewal. Conversely, reduced pyruvate entry via MPC in NPCs can trigger loss of quiescence in the NPCs, resulting in the maturation to intermediate NPCs and eventually mature nerve cells. IMM, inner mitochondrial membrane; IMS, mitochondrial intermembrane space; and OMM, outer mitochondrial membrane. Refs. , are cited in this figure.

Fig. 2 ∣. Adipocyte plasticity in tissue remodelling.

a, Beige progenitor cell proliferation, differentiation and beige-to-white fat conversion. Stimulation of the β-3 adrenergic receptor (β3-AR) via norepinephrine results in lipolysis and release of free fatty acids, which signal to adipose progenitors via internalization by CD36. This drives proliferation and mitochondrial biogenesis of beige progenitors and subsequent differentiation to beige adipocytes. White adipocytes can transdifferentiate to beige via factors that induce mitochondrial biogenesis. Beige adipocytes can undergo transdifferentiation to white via mitophagy-mediated clearance of mitochondria. b, Adipose tissue of lean individuals is more insulin-sensitive than adipose of obese individuals. Adipose of obese individuals has a more inflammatory phenotype, with increased macrophage recruitment and subsequent stiff ECM deposition as a result of tissue hypoxia. Mitochondrial oxidative capacity and lipid oxidation is higher in lean individuals as opposed to obese individuals.

Fig. 3 ∣. Exercise-adapted versus sedentary mitochondria.

There is preferential reliance on OXPHOS activity and an increased propensity for fatty acid oxidation, underscored by increased expression of CPT1, in mitochondria that are in exercise-adapted skeletal muscle. As a result, there is reduced preference for anaerobic glycolysis and therefore, glucose utilization. Furthermore, more mitochondrial fusion driven by the proteins OPA1 and MFN1 occurs, which also increases cristae density. There is also increased Ca²⁺ import into the mitochondria. Mitochondrial–nuclear crosstalk results in increased mitochondrial biogenesis, which is in part driven by PGC-1α. Conversely, there is a strong preference for anaerobic glycolysis, as a result of rapid glycogen mobilization, in mitochondria in skeletal muscle of sedentary individuals. The glycogen-derived glucose is converted to lactate in the cytosol, which is transported into the intermembrane space via the action of monocarboxylate transporter 1 (MCT1). The lactate is converted to pyruvate via lactate dehydrogenase B (LDHB) in the IMS and the resulting pyruvate is transported into the matrix via the MPC. Pyruvate dehydrogenase (PDH) takes this pyruvate and feeds the TCA cycle via acetyl-CoA. There is reduced oxidative capacity and enhanced ROS production as well as decreased lipid oxidation capacity, in part driven by lower expression of CPT1. Enhanced fission results in degradation by mitophagy.

Fig. 4 ∣. Mitochondrial fuel source selection in the fed versus fasted state.

In the fed state, glucose is quickly converted to glucose-6-phosphate (G6P), demonstrated by the thick dark blue arrow to demonstrate fuel preference, which allosterically regulates glycogen synthase in the cytosol to promote glycogen synthesis. Malate is imported into mitochondria and converted to OAA, which fuels the TCA cycle. PEPCK-M activity is reduced in the fed state and the conversion of OAA to PEP is similarly reduced. PEP export out of the mitochondria, which would normally fuel glucose production, is reduced in the fed state, as demonstrated by the grey arrows. Glucose-derived pyruvate is transported into the mitochondria via the MPC in increased amounts, as demonstrated by the thick dark blue arrows. This pyruvate subsequently fuels TCA cycle activity. In the fasted state, glycogen-derived pyruvate is imported into mitochondria, which is converted to OAA by pyruvate carboxylase (PC). This OAA is converted to PEP via enhanced activity of PEPCK-M in response to fasting and the PEP is exported out of the mitochondria to fuel gluconeogenesis. OAA-derived malate is similarly exported out of the mitochondria.