Beyond ATP, new roles of mitochondria

Abstract

Mitochondria, special double-membraned intracellular compartments or 'organelles', are popularly known as the 'powerhouses of the cell', as they generate the bulk of ATP used to fuel cellular biochemical reactions. Mitochondria are also well known for generating metabolites for the synthesis of macromolecules (e.g., carbohydrates, proteins, lipids and nucleic acids). In the mid-1990s, new evidence suggesting that mitochondria, beyond their canonical roles in bioenergetics and biosynthesis, can act as signalling organelles began to emerge, bringing a dramatic shift in our view of mitochondria's roles in controlling cell function. Over the next two and half decades, works from multiple groups have demonstrated how mitochondrial signalling can dictate diverse physiological and pathophysiological outcomes. In this article, we will briefly discuss different mechanisms by which mitochondria can communicate with cytosol and other organelles to regulate cell fate and function and exert paracrine effects. Our molecular understanding of mitochondrial communication with the rest of the cell, i.e. mitochondrial signalling, could reveal new therapeutic strategies to improve health and ameliorate diseases.

Figure 1.. Mitochondria as bioenergetic and biosynthetic organelles.

Mitochondria generate ATP through oxidative phosphorylation (a) and TCA cycle metabolites to support macromolecule synthesis for biomass production (b).

Figure 2.. Mitochondria as signalling organelles.

Mitochondrial reactive oxygen species (ROS), metabolites, nucleic acids, proteins and peptides, NADH/NAD⁺ ratio and morphological dynamics can act as signals to regulate various cellular processes. AMPK: AMP-activated protein kinase; HRI: heme-regulated inhibitor; GCN2: general control nonderepressible 2; MAVS: mitochondrial antiviral-signalling protein; STING: stimulator of interferon genes; TLR9: toll-like receptor 9; NLRP3: NOD-, LRR- and pyrin domain-containing protein 3.

Figure 3.. Mitochondrial dynamics dictate cell fate and function.

Mitochondria are morphologically very dynamic. They can relay signals to other parts of the cells by changing their shapes through cristae remodeling as well as the opposing fusion and fission processes to dictate cell fate and function. MFN1/2: mitofusin 1/2; OPA1: optic atrophy-1; Drp1: dynamin-related protein 1.

Figure 4.. Mitochondria–organelles interactions regulate different cellular processes.

Mitochondria can communicate with other cellular organelles by forming physical contacts to regulate various cellular processes.

Figure 5.. Mitochondrial signalling can systemically regulate physiological and pathological processes.

Mitochondrial stress can induce a cell to release signalling molecules dubbed ‘mitokines’ (e.g., succinate and GDF15) that often act on other cells in a paracrine manner to dictate physiological and pathological outcomes. ISR: integrated stress response; ATF4: activating transcription factor 4; GDF15: growth differentiation factor 15; SUCNR1: succinate receptor 1; GFRAL: GDNF (glial cell line-derived neurotrophic factor) family receptor α-like.