Multifaceted mitochondria: moving mitochondrial science beyond function and dysfunction

Abstract

Mitochondria have cell-type specific phenotypes, perform dozens of interconnected functions and undergo dynamic and often reversible physiological recalibrations. Given their multifunctional and malleable nature, the frequently used terms 'mitochondrial function' and 'mitochondrial dysfunction' are misleading misnomers that fail to capture the complexity of mitochondrial biology. To increase the conceptual and experimental specificity in mitochondrial science, we propose a terminology system that distinguishes between (1) cell-dependent properties, (2) molecular features, (3) activities, (4) functions and (5) behaviours. A hierarchical terminology system that accurately captures the multifaceted nature of mitochondria will achieve three important outcomes. It will convey a more holistic picture of mitochondria as we teach the next generations of mitochondrial biologists, maximize progress in the rapidly expanding field of mitochondrial science, and also facilitate synergy with other disciplines. Improving specificity in the language around mitochondrial science is a step towards refining our understanding of the mechanisms by which this unique family of organelles contributes to cellular and organismal health.

Fig. 1 |. An integrative approach to mitochondrial biology.

a–c, There are organ-specific domains of human health that guide medical investigation and practice (a), cell-type-specific domains of cell biology that guide biological theories and research practices (b) and domains of mitochondrial biology that guide mitochondrial science (c). d, Blind men–here scientists blindfolded by their perspective limited by prevailing theories, training and career history, available instrumentation and/or analytical methods–make valid observations about specific aspects of the animal under study. However, without a global perspective enabling them to perceive the whole animal at once, an error of logic is committed, leading to erroneous induction and conclusions, drawn from its parts, about the nature of the whole organism. e, The same type of limitation exists when examining mitochondria with different instruments that are blind to other aspects of mitochondrial biology, for example, microscopy, biochemistry, genomics and metabolomics. Focused reductionist approaches are necessarily undertaken blind to other domains of function or behaviour, yielding partially valid conclusions and, when taken in isolation, a largely inaccurate picture of the system/organelle. The history of mitochondrial research illustrates the need for interdisciplinary approaches and sufficiently specific terminology to examine mitochondrial biology and its contribution to human health. ROS, reactive oxygen species; MDVs, mitochondria-derived vesicles; TEM, transmission electron microscopy; Cyt c, cytochrome c.

Fig. 2 |. Different cell types and subcellular compartments contain functionally specialized mitochondrial phenotypes.

a, Despite originating from the same progenitor haematopoietic stem cell, differentiated human circulating leucocyte subtypes exhibit distinct mitochondrial content and respiratory chain properties. b,c, Bivariate plots illustrating quantitative differences in mtDNAcn, CS activity and OxPhos complex I enzymatic activity. Data for eight different human cell subtypes, plus the heterogeneous cell mixture in peripheral blood mononuclear cells (PBMCs), were isolated using FACS. Data are from ref. . Note the clustering of similar mitochondrial phenotypes according to known immunological and immunometabolic differences between naïve and memory cells, or between cell subtypes belonging to the innate and adaptive arms. d, Functional differences among rat skeletal muscle mitochondria between glycolytic (type II, fast-twitch) and oxidative (type I, slow-twitch) muscle fibres. e–g, Three mitochondrial functions are shown: the sensitivity of respiration (e) to ADP concentration and presence of creatine (Cr), where a low Michaelis constant (Km) means that high respiratory rates are driven by little ADP; ROS emission (f), H₂O₂ release per unit of mitochondrion indexed by CS; the total amount of Ca²⁺ uptake (g) that mitochondria can sustain before undergoing PTP opening. −Cr, no creatine; +Cr, with creatine; wGas, white gastrocnemius (type II); Sol, soleus (type I); EDL, extensor digitorum longus (type II); AL, adductor longus (type I). Data are from ref. . h, Mouse adipocytes contain at least two different types of mitochondria: PDM and non-PDM (cytoplasmic). i,j, Biplots representing (i) the maximal rate of ATP synthesis and maximal oxygen consumption rate (OCR; i) or size versus motility (j). Data are from refs. ,. NK, natural killer.

Fig. 3 |. Diversity in mitochondrial morphology.

a, TEM micrographs of mitochondria in mammalian tissues and cultured cells. The 143B-ρ⁰ mitochondrion lacking mtDNA is from ref. . Adrenal mitochondrion reproduced with permission from ref. . Liver, pancreas, brown adipocyte and Leydig cell mitochondria reproduced with permission from ref. ; other images are from M.P.’s laboratory). Note the natural variation in morphology (gross shape of mitochondria), in ultrastructure (positioning and organization of internal cristae membranes) and overall electron density (reflecting density of molecular components). b,c, Three-dimensional reconstructions (b) of neural mitochondria from the subcellular compartments of large granule neurons in the mouse dentate gyrus (adapted from ref. 85), and of skeletal muscle (c) mitochondrial phenotypes between the SS and IMF regions of human skeletal muscle fibres (adapted from ref. 86). Note the variation in morphological complexity and volume within the mitochondrial population of the same cell.

Fig. 4 |. Terminology for mitochondrial science organized as a hierarchy of mitochondrial needs.

a, inspired by Maslow’s pyramid of human needs, depicted is a hierarchy of biological organization from molecules to complex organellar behaviours. Lower levels combine to enable higher levels of organization. Each level can be studied using specific types of laboratory methods and analytical approaches. Thus, different approaches provide different types of information about the molecular features, activities, functions and behaviours that define specific mitochondrial phenotypes. b, Operationalization and examples for different levels of organization available to examine and perturb mitochondrial biology. Biomedical terminology related to organismal characteristics (left), and terminology related to cell biology (middle) are provided as parallel illustrative examples at each level of description for mitochondrial biology.

Fig. 5 |. Example of measurements across domains of mitochondrial biology.

Cell-dependent phenotypes: Frequently used mitochondrial measures such as mitochondrial content (also known as mitochondrial mass), mtDNAcn per cell, and OCR by cells or tissues do not reflect intrinsic mitochondrial properties. Rather, they provide information about cellular energy demand and/or cell-level regulatory processes controlling mitochondrial biology. Features: Features are molecular components that can vary in quantity or quality, generally measurable from frozen or dead cellular material. Activities: Activities emerge from the interaction of multiple features, resulting in specific enzymatic activities or intrinsic properties of mitochondria that change the effective concentration of one or more substrates. Functions: Functions emerge from the combination of several activities, resulting in the transformation of inputs into outputs at the organelle level. Example of activities include energy transformation through the OxPhos system, Ca²⁺ regulation, macromolecule biosynthesis and the production of signals or outputs. Behaviours: Behaviours emerge from the interaction of multiple functions in collaboration with cytoplasmic and inter-organellar factors. As in cells and organisms, behaviours are best understood as goal driven, meaning that they reflect the coming together of several functions towards an end goal, such as modulating the architecture of the mitochondrial network through dynamics and motility, altering nuclear gene expression through repositioning and signalling, or optimizing cellular and organismal adaptation through inter-organelle and cell–cell communication. For a list of mitochondrial functions and behaviours, see Table 1. SNP, single-nucleotide polymorphism; MCU, mitochondrial calcium uniporter; ISR, integrated stress response; IMJ intermitochondrial junctions.