Shapeshifters of the Cell: The Diverse Forms and Functions of Mitochondria

One of the most memorable images for every high school biology student is the neat, oviform 'powerhouse of the cell' - the mitochondrion. However, this image is grossly deficient; since scientists first observed mitochondria in the 1850s (Atlante and Valenti, 2023), our knowledge of their contents, structures, and purpose has profoundly changed and expanded. We now understand that alongside this organelle's primary role in energy metabolism, they possess a myriad of other roles, including intracellular reactive oxygen species (ROS) generation and apoptosis (Wen, Zhao and Li, 2023). Particularly fascinating are the numerous shapes that they morph into and how these relate to their functions.

Contrary to the simplistic oval depiction, mitochondria exhibit a remarkable diversity in their architectures, ranging from elongated tubules and branched networks to consolidated spheres and even intricate, interconnected arrangements (Glancy et al., 2020). This plasticity reflects the organelle's crucial role in cellular energy pathways and its dynamic adaptation to the specific functional requirements of diverse cell types and environmental conditions.

The shape and size of mitochondria are not merely passive attributes, but are actively regulated by a meticulous harmony of fusion and fission events - the former allows individual mitochondria to merge, creating elongated, interconnected networks, while fission results in the division of these organelles into smaller, more dispersed units.

Both processes are powered by guanosine triphosphate (GTP), the guanine-containing counterpart of adenosine triphosphate (ATP), and utilise a complex array of proteins; mitofusins propagate the gradual fusion of the outer mitochondrial membranes (OMMs) while fission uses the dynamin-like protein Drp1 - dysregulation of proteins employed in either process results in abnormally swollen or elongated mitochondria (Glancy et al., 2020)(Westermann, 2010). This dynamic interplay is crucial for maintaining mitochondrial function, distribution, and intracellular quality control.

Controlling surface area and volume are the principal objectives of fission and fusion. Mitochondria with a greater volume have increased functional capacity, but smaller organelles are more manageable to remove and leave more space in the cell for other sub-cellular structures (Glancy et al., 2020). Elongated mitochondria have a larger external surface area, i.e., a more extensive outer mitochondrial membrane (OMM), allowing for more interaction with the external environment, as, for example, there is an increased rate of diffusion of signalling molecules into the organelle. However, this diminishes internal functional capacity. Resultantly, mitochondria may be denser in tissues where this is a more pertinent issue.

Internal surface area is an equally consequential factor; this is grown by increasing the number of folds in the inner mitochondrial membrane (IMM) (Glancy et al., 2020). These folds are known as cristae and are used to house several transmembrane proteins essential for key mitochondrial processes - primarily energy conversion. More cristae, therefore, will result in a higher rate of these processes - when mitochondria fuse or grow, they become loaded with additional cristae. In some cases, however, matrix volume is prioritised to improve signalling and biosynthesis capabilities (Glancy et al., 2020).

If we examine a little deeper, the morphology of the cristae also plays a vital role in mitochondrial functionality. Again, such critical details are woefully absent from pre-university textbooks. Broadly, there exist three categories of cristae by shape: lamellar (flat), vesicular (bubble, ampule, or sac-like), and tubular (Seravin, 1993). Vesicular cristae are those that are detached from the continuous internal membrane. Their formation is thought to be a component of the mitochondrial quality control process, possibly involved in recycling (Liesa, 2020), and a precursor to mitochondrial fragmentation, which is necessary for apoptosis (Mannella, 2008), the process of 'programmed cell death' (Elmore, 2007). The purpose of both lamellar and tubular cristae is to accommodate electron transport chain (ETC) complexes and ATP synthase proteins (Glancy et al., 2020), which are necessary to generate ATP, which supplies the cell with metabolic energy for processes such as muscle contraction, nerve impulse propagation, and protein synthesis (Dunn and Grider, 2023) - this is at the core of mitochondrial function. However, for unclear reasons, certain tissues have a greater proportion of one over the other - pancreatic cells, for instance, contain predominantly lamellar cristae, whereas steroidogenic cells, for example, those in the ovaries and testes, possess mainly tubular cristae (Harner et al., 2016b).

Another striking feature of mitochondria is nanotunnels - narrow double-membrane protrusions connecting the matrices of multiple non-adjacent mitochondria (Vincent et al., 2017). These unique structures either form de novo or arise from stalled fission events. They allow distant mitochondria to disseminate matrix and membrane proteins, ions, and other resources among each other, in addition to providing a more controlled channel of intermitochondrial communication - signals, such as those triggering apoptosis or continued fission, travel slower through nanotunnels due to their minuscule diameter of >100nm (Madreiter‐Sokolowski et al., 2019). Nanotunnels are thus an integral component of mitochondrial plasticity.

Different tissues have distinct mitochondrial characteristics. Neurons display notably diverse mitochondrial morphologies owing to their unique structure. Dendrites, the branched projections of the neuron which relay electrical signals received from other nerve cells to the soma (cell body), possess long tubular mitochondria (Lewis et al., 2018). Conversely, mitochondria in the axon, the cable which transmits action potentials away from the soma are uniformly short. Of particular interest, however, are those near the presynaptic terminal - elongation of mitochondria in this region increases mitochondrial Ca2+ uptake, reducing presynaptic Ca2+ accumulation, thereby stymying neurotransmitter release, which requires a buildup of Ca2+ (Mochida, 2019). This ability is augmented by a greater capacity to store Ca2+, which results from increased matrix volume. Buffering Ca2+ permits neurons to exercise greater control over the signals that they deliver.

In contrast, hepatocytes (cells in the liver) are filled with diminutive globular or tube-like mitochondria (Das et al., 2012) that are evenly dispersed throughout the cytoplasm (Glancy et al., 2020). The compactness liberates space for other organelles, such as the Golgi apparatus, which is particularly important for the liver's role in synthesising vital enzymes, and the distribution may reflect their comparatively isotropic function.

Skeletal muscle possess one of the quirkiest and most specialised mitochondrial structures. Several distinct tubular mitochondria are densely packed into columns between myofibrils, forming an almost continuous network (Vincent et al., 2019). Resultantly, aerobic respiration can occur at an optimum rate, and the distance that ATP has to travel to reach the area it is needed the most is minimised.

Another level upwards, mitochondrial plasticity is fundamental to whole body systems. A primary example of this is the immune system. Upon recognising complementary antigens on a pathogen, T cells become activated, differentiating into effector T cells - which either kill the foreign cell or release signalling molecules to coordinate the immune response - and dividing rapidly. Although most effector T cells die after an infection is resolved, a few become memory T cells - this process enhances protective immunity against previously encountered pathogens. Before activation, T cells use mostly fatty acid oxidation (FAO), the aerobic breakdown of fatty acids into acetyl-CoA units (Jones, Patel and Rakheja, 2020), and oxidative phosphorylation (OXPHOS), the process of generating ATP through the electron transport chain's reduction of oxygen, to meet their metabolic requirements (Angajala et al., 2018)(Xie et al., 2020). Post-activation, they rely more on glycolysis, the conversion of glucose to lactate. The mitochondrial figure reflects this transition - activation triggers fission and reduced cristae formation, as there is a reduced need for ETC complexes. After reprogramming to become memory cells, more fused mitochondria are present due to a renewed dependence on FAO.

B cells have a similar life cycle, with an inactive form stimulated to divide as part of the immune response and the formation of memory B cells. However, the primary role of B cells is the generation of antibodies, which latch onto the foreign antigens. The metabolic metamorphism that B cells display is parallel to that of T cells; in their inactive form, they have fewer mitochondria, reflecting their low energy requirement, that are markedly elongated, and after activation, these mitochondria divide and become more rounded (Xie et al., 2020), possibly to allow more space for organelles like the endoplasmic reticulum to synthesise and release more antibodies.

Mitochondrial shape change is essential for a cell's reaction to challenging conditions. Starvation triggers autophagy, which involves the degradation of organelles by autophagosomes - unique vesicles which envelop cellular material and ferry it to lysosomes for digestion (Nakatogawa, 2020) - to salvage scarce nutrients. In response, mitochondria stretch into long tubular structures to protect themselves (Glancy et al., 2020). On the other hand, hyperglycemia - high blood sugar - results in mitochondria fragmenting to increase respiration rate and normalise glucose levels (Glancy et al., 2020). However, this also leads to a surge in reactive oxidative species (ROS) production, which induces cellular damage and is a hallmark of metabolic diseases such as diabetes (Galloway & Yoon, 2015). Consequently, researchers have explored targeting mitochondrial morphology-regulating proteins directly to stymie the impacts of such illnesses.

Such responses to harsh situations are often unique for certain organs or tissues. For instance, the mitochondria in cardiomyocytes fragment as a reaction to ischemia (a restriction of blood supply) or reperfusion injury, in which blood supply returns to cells after a period of ischemia, resulting in an upsurge in oxygen and ROS concentrations, which exacerbates cellular damage (Cowled and Fitridge, 2011). This phenomenon is thought to be a mechanism to segregate irreparably damaged sections of mitochondria for autophagy (Ikeda et al., 2015). A notably peculiar example of a tissue-specific response is in the liver; under stress, their typically spherical mitochondria contort into doughnut or c-shaped structures (Glancy et al., 2020). Although the precise reason for this transition is currently unknown, Ahmad et al. (2013) proposed that the extent of this change could be analysed by computational methods to determine the exact degree of cellular stress.

Furthermore, mitochondria often display abnormal and undesirable features in several diseases. In particular, neurodegenerative ailments progression is closely intertwined with abnormal mitochondrial morphology and operation. Alzheimer's disease (AD), which is characterised by memory loss and broad cognitive impairment, is linked to several signs of mitochondrial dynamics dysfunction. Over-expression of amyloid-beta precursor protein (APP), which is a forerunner for amyloid plaques, the deposits of misfolded protein that play a central role in the development of AD, causes a surge in mitochondrial fission, disrupts mitochondrial positioning and hinders quality control, resulting in accelerated neurodegeneration (Yang et al., 2021), due to the hindered energy metabolism of neurons. Additionally, AD has been linked to an uptick in the frequency of broken cristae (Wen, Zhao and Li, 2023b), exacerbating the issue. Parkinson's disease and Huntington's disease also display notably abnormal mitochondrial fragmentation - in the former, damage to the electron transport chain leads to additional oxidative stress.

Over the past few decades, knowledge of mitochondrial dynamics has been leveraged to design novel therapies to ameliorate, or even cure the aforementioned conditions. Several small molecules which target the fundamental proteins of fission and fusion have been identified - mdivi-1 (mitochondrial division inhibitor 1), for example, has been demonstrated to act as a GTPase inhibitor (preventing GTP from being hydrolysed for mitochondrial fragmentation)(Zacharioudakis and Gavathiotis, 2023). Promisingly, it has displayed protective effects against ischemia-reperfusion injury and traumatic brain injury in mice, although its development as a useable therapy is nascent, currently in the pre-clinical trial phase. Mitofusin activators such as MASM7, which have similar effects, have been shown to improve neuromuscular integrity and regrowth of neurons - they, too, await clinical trials.

In conclusion, the simple oval depiction of mitochondria, while convenient for introductory textbook illustrations, fails to capture the true complexity and significance of these remarkable organelles. By peeling back the layers of the intricate biological phenomenon of mitochondrial plasticity and delving into its functional implications, we inch closer to unravelling the mysteries of health and disease and pave the way for groundbreaking advancements in medicine and biotechnology.