Causal roles of mitochondrial dynamics in longevity and healthy aging

Abstract

Mitochondria are organized in the cell in the form of a dynamic, interconnected network. Mitochondrial dynamics, regulated by mitochondrial fission, fusion, and trafficking, ensure restructuring of this complex reticulum in response to nutrient availability, molecular signals, and cellular stress. Aberrant mitochondrial structures have long been observed in aging and age-related diseases indicating that mitochondrial dynamics are compromised as cells age. However, the specific mechanisms by which aging affects mitochondrial dynamics and whether these changes are causally or casually associated with cellular and organismal aging is not clear. Here, we review recent studies that show specifically how mitochondrial fission, fusion, and trafficking are altered with age. We discuss factors that change with age to directly or indirectly influence mitochondrial dynamics while examining causal roles for altered mitochondrial dynamics in healthy aging and underlying functional outputs that might affect longevity. Lastly, we propose that altered mitochondrial dynamics might not just be a passive consequence of aging but might constitute an adaptive mechanism to mitigate age-dependent cellular impairments and might be targeted to increase longevity and promote healthy aging.

Keywords: aging; fission; fusion; mitochondria; mitochondrial dynamics.

Figure 1. Mitochondria perform a variety of functions that are essential for cellular health

As the metabolic hub of the cell, mitochondria have many roles beyond ATP generation such as the production of intermediate metabolites, inter‐organelle signaling, and Ca²⁺ and ROS homeostasis. All of the functions listed here are interconnected, dependent upon both the integrity of individual mitochondria and the integrity of the entire mitochondrial network. Additionally, these processes are dysregulated with age. Age‐related changes in mitochondrial fission and fusion may contribute to the impairment of these mitochondrial functions.

Figure 2. Mechanism of mitochondrial fission and fusion

(A) Mitochondrial fission is initiated by endoplasmic reticulum (ER, blue)‐dependent or endoplasmic reticulum‐independent mechanisms. Receptor proteins such as mitochondrial fission factor (MFF), mitochondrial fission 1 protein (FIS1), mitochondrial dynamics protein 49 (MiD49), and mitochondrial dynamics protein 51 (MiD51) recruit the cytosolic scission factor dynamin‐related protein 1 (DRP1). Once localized to the mitochondria, DRP1 multimerizes to form spirals on the outer mitochondrial membrane (OMM), hydrolyzes GTP, and causes mitochondrial constriction. Dynamin‐2 is then recruited and orchestrates sequential constriction leading to mitochondrial division. These events are followed by disassembly of the fission proteins that translocate to the mitochondria and a decrease in ER‐mitochondrial tethering. (B) Mitochondrial fusion begins with tethering of two separate mitochondrion via outer membrane tethering mitofusins (MFN1/2). Successful tethering and OMM fusion are followed by the fusion of inner mitochondrial membrane (IMM) mediated by the protein OPA1 resulting in fusion of two separate mitochondrion.

Figure 3. Mitochondria‐ER crosstalk

Mitochondria and ER exist in close proximity with each other forming mitochondria‐associated membranes (MAMs). MAMs are enriched with mitochondria‐specific proteins such as voltage‐dependent anion channel (VDAC) and mitofusin 1/2 (MFN), ER‐specific proteins such as sarco/endoplasmic reticulum Ca²⁺‐ATPase (SERCA), inositol 1,4,5‐trisphosphate (IP3R), calnexin, and calreticulin. Tethering proteins such as glucose‐regulated protein 75 (GRP75) stabilize MAM structures, while proteins such as FUNDC1 translocate to MAMs. MAMs allow efficient Ca²⁺ homeostatic exchange between ER and mitochondria through IP3R VDAC mitochondria calcium uniporter (MCU) and permeability transition pore (PTP) and SERCA. In addition to MAMs, ER forms direct contacts with mitochondria and mark sites for mitochondrial fission and ER‐specific inverted formin 2 (INF2) can cause actin‐dependent constriction of mitochondria to initiate mitochondrial fission. Several proteins involved in mitochondrial fission such as mitochondrial fission factor (MFF) and mitochondrial fission 1 protein (FIS1) mediate dynamin‐related protein 1 (DRP1) localization on ER suggesting that additional unidentified pathways by which ER controls mitochondrial dynamics exist.

Figure 4. Peroxisomes are dynamic organelles that share fission machinery with mitochondria

Peroxisomes modulate their morphology, abundance, and function through coordinated cycles of growth, elongation, and fission. The regulation of peroxisome membrane dynamics is intimately tied to mitochondrial dynamics, as the mechanism of peroxisome membrane fission largely parallels that of mitochondrial fission. The protein machinery controlling mitochondrial fission, namely DRP1, FIS1, and MFF, is also required for peroxisome membrane fission. FIS1 and MFF are C‐terminal‐anchored membrane adaptor proteins that facilitate recruitment of and interaction with DRP1 and PEX11 at sites of fission. PEX11 is required for the initial phase of peroxisome fission, where it initiates the formation and elongation of nose‐like protrusions from the spherical membrane. Pex11 has also been reported to generate sites of constriction along these protrusions, and contributes to the recruitment and activity of DRP1. Final scission of peroxisome membranes is catalyzed by assembly of DRP1 ring structures and GTP hydrolysis.